Purified cenicriviroc and purified intermediates for making cenicriviroc

ABSTRACT

The disclosure includes high purity compounds having CCR5 and/or CCR2 antagonism, or salts thereof, high purity intermediates thereto and processes for synthesizing the same.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/628,968 filed Jun. 21, 2017, which claims the benefit of priority toU.S. Provisional Patent Application No. 62/352,885 filed Jun. 21, 2016,the disclosures of which is hereby incorporated by reference in itsentirety for all purposes.

FIELD

The present disclosure relates to purified compounds having CCR5 and/orCCR2 antagonism, or a salt thereof, and purified intermediates formaking the compounds.

BACKGROUND

It is known that cenicriviroc (CVC) inhibits CCR5 and CCR2 receptors andprevents virus from entering into a human cell, such as the HIV virus(U.S. Pat. No. 8,183,273). The synthesis of CVC is also previouslydisclosed in U.S. patent application Ser. No. 10/506,955 and Int. Pat.Pub. No. WO 2001017947.

The present disclosure provides for purified CVC, CVC salts, includingCVC methane sulfonic acid salt, or related analogs, and purifiedintermediates for preparing the aforesaid.

Conventional methods of synthesizing CVC, CVC salts, and relatedanalogs, resulted in the presence of undesirable impurities. Thus, thereis a need for highly pure CVC, purified intermediates thereto andprocess of making the same.

SUMMARY OF THE DISCLOSURE

This disclosure is directed to highly purified Compound I, a racemic oroptically pure form of CVC, and the formation of its methane sulfonicacid salt (Compound I-MsOH) and highly purified intermediate compound IIuseful for preparing Compound I, and the process for making them. Insome embodiments, Compound I and Compound I-MsOH are racemic. In otherembodiments, Compound I and Compound I-MsOH comprises an opticallyactive sulfoxide, such as the (S)-isomer denoted as (S)-Compound I-MsOH.

Compound I is synthesized by a reaction between Compound II and CompoundIII:

wherein R₁ is selected from the group consisting of H, OH, Cl, Br, OR₂,OCOR₂, and NHR₂; and

wherein R₂ is selected from the group consisting of H, alkyl,substituted alkyl, aryl, and substituted aryl.

Compound I is synthesized by a reaction between Compound II where R₁═OH(Compound II-OH) and Compound III.

Compound II-OH is synthesized by a reaction between Compound IV andCompound V and/or Compound V-3:

wherein R₃ is Ar₁ or OR₅; R₄ is Ar₂ or OR₆; and R₅, and R₆ areindependently selected from the group consisting of H, alkyl, andsubstituted alkyl; or R₅ and R₆ together forms an optionally substitutedalkyl or an optionally substituted aryl; Ar₁ and Ar₂ are independentlyaryl or substituted aryl.

In some embodiments, R₃ and R₄ are both OMe or both OH for Compound V,which are denoted as Compound V-OMe or Compound V-OH, respectively.

In some embodiments, Compound V is synthesized from Compound VI.

This disclosure is directed to a process route to minimize impuritiesrepresented by Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-D,I-MsOH-E, (R)-I-MsOH, VII, VIII, IX, and mesylate esters resulting fromMsOH.

The present disclosure includes a process for preparing highly purified8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH). For example, the synthesis ofCompound I-MsOH includes formation of dimethyl(4-(2-butoxyethoxy)phenyl)boronate (Compound V-OMe) which issubsequently used in formation of highly pure8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH).

Compound I-MsOH is prepared from (4-(2-butoxyethoxy)phenyl)boronate(Compound V-OMe) and/or (4-(2-butoxyethoxy)phenyl)boronic acid (CompoundV-OH) and/or2,4,6-tris(4-(2-butoxyethoxy)phenyl)-1,3,5,2,4,6-trioxatriborinane(Compound V-3). Compound I-MsOH is prepared from Compound V-OH and/orCompound V-3. Compound I-MsOH is prepared from Compound V-OH and/orCompound V-3 which is essentially free of Compounds V-A, V-B, and/orV-C:

-   -   wherein R₃ and R₄ are both OMe or OH.

In some embodiments, Compound V is prepared by a) activating magnesiumin tetrahydrofuran (THF) with heating, b) initiating Grignard formationby the addition of a portion of 1-bromo-4-(2-butoxyethoxy)benzene(Compound VI) to a mixture of step a) with heating, c) continuing to addthe remaining Compound VI slowly with heating, d) cooling the mixture ofstep c) to about −25° C. and slowly adding trimethoxyborane, and e)stirring the mixture of step d at about −25° C. for about 1 hour andthen warming up the reaction to about 20° C. for about 1 hour.

In some embodiments, the molar ratio of Compound VI and trimethoxyboraneused is about 1:1.

In some embodiments, neat Compound VI is used in steps b) and/or c). Inother embodiments, step c) requires reaction to stir at about 55° C. forabout 3 hours to about 5 hours.

Compound V synthesized as described herein, in one embodiment, is thenutilized in the synthesis of Compound II-OH. In some embodiments,Compound II-OH is prepared by a) forming a biphasic mixture by adding abasic aqueous solution to a solution of Compound V, b) adding a catalystand a ligand to mixture of step a), c) adding8-bromo-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid(Compound IV) to the mixture of step b) and heating the reactionmixture, and d) acidifying the mixture of step c). The base used in stepa), in some embodiments, is selected from the group consisting ofpotassium phosphate, potassium carbonate, potassium acetate, potassiumfluoride, potassium hydroxide, potassium tert-butoxide, sodiumcarbonate, sodium phosphate, sodium hydroxide, sodium tert-butoxide,sodium bicarbonate, cesium carbonate, cesium fluoride, and a combinationthereof. In some embodiments, the catalyst used in step b) is selectedfrom the group consisting of palladium acetate,tetrakis(triphenylphosphine) palladium,tri(dibenzylideneacetone)dipalladium, palladium chloride, palladiumacetylacetonate and a combination thereof. In some embodiments, theligand used in step b) is selected from the group consisting oftri(o-tolyl)phosphine, triphenylphosphine, tri(t-butyl)phosphine,tricyclohexylphosphine, pyridine, bipyridine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and a combination thereof.In another embodiment, the catalyst system of step b) comprisespalladium acetate and tri(o-tolyl)phosphine.

In some embodiments, the ratio of catalyst to ligand is about 1:2. Inother embodiments, the catalyst used in step b) is in an amount fromabout 0.001 equivalents (equiv) to about 2.500 equiv with respect toCompound IV. In a further embodiment, the catalyst is used in an amountof about 0.001 equiv to about 0.005 equiv with respect to Compound IV.In some embodiments, nitrogen is bubbled into the reaction after step a)up to step d) or during any steps a) through d).

In some embodiments, Compound V is used in an amount of about 1.5 equivto about 2.2 equiv with respect to Compound IV in the formation ofCompound II-OH. In another embodiment, the heating of step c) ismaintained at ≤65° C. for about 2 hours to about 6 hours and ensuredhigh conversion to Compound II-OH.

In other embodiments, during purification step after step d), charcoalis added, with or without Celite® to the reaction mixture containingCompound II-OH. In another embodiment, the mixture containing charcoaland/or Celite® and Compound II-OH is stirred, and then filtered. In oneembodiment, the ratio of charcoal to Celite® is about 1:2.

In another embodiment, during purification step after step d), Celite®is added to the reaction mixture containing Compound II-OH, stirred, andthen filtered. In one embodiment, during the purification step afterstep d), the reaction mixture is filtered to remove any solidparticulates.

In some embodiments, purification of Compound II-OH involves anantisolvent recrystallization and/or a hot recrystallization. In someembodiments, the antisolvent used in the antisolvent recrystallizationis heptane, to obtain a crude material. In other embodiments, hotrecrystallization involves the steps of i) dissolving crude materialobtained from antisolvent recrystallization with a non-protic polarsolvent and a short-chain alcohol at about 70° C., ii) reducing thetemperature of the mixture of step i) to about 20° C. over a period ofabout 3 hours to about 7 hours, and iii) stirring the mixture of stepii) at about 20° C. for about 2 hours to about 6 hours. In oneembodiment, the non-protic solvent is ethyl acetate. In anotherembodiment, the short-chain alcohol is isopropanol.

The present disclosure further describes the process for the preparationof8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH). The disclosed process forsynthesizing Compound I-MsOH involves a) reacting Compound II with4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) inthe presence of a base to form8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide(Compound I), b) quenching step a) with an aqueous solution, c) addingmethanesulfonic acid, and d) crystallizing Compound I-MsOH. In someembodiments, R₁ of Compound II is selected from the group consisting ofH, OH, Cl, Br, OR₂, OCOR₂, and NHR₂, and R₂ of Compound II is selectedfrom the group consisting of H, alkyl, substituted alkyl, aryl, andsubstituted aryl.

In some embodiments, R₁ of Compound II is Cl. In one embodiment,synthesis of Compound II involves the steps of i) dissolving CompoundII-OH in a solvent and ii) adding a chlorinating reagent to the mixtureof step i). In some embodiments, the chlorinating reagent is selectedfrom the group consisting of thionyl chloride, phosphorous trichloride,phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride,phosgene, and a combination thereof.

In one embodiment, the chlorinating reagent is thionyl chloride. In someembodiments, the chlorinating reagent is used in about 1.0 equiv toabout 1.2 equiv with respect to Compound II-OH.

In some embodiments, step a) of the synthesis of Compound I-MsOH usesdichloromethane as the solvent. In other embodiments, step a) synthesisof Compound I-MsOH uses pyridine as the base. In another embodiments,step a) synthesis of Compound I-MsOH uses optically pure (S)-CompoundIII as Compound III.

In some embodiments, the amount of Compound III used is about 1.0 equivto about 1.2 equiv with respect to Compound II-OH. In some embodiments,the amount of methane sulfonic acid used is about 0.97 equiv to about1.02 equiv with respect to Compound II-OH. In other embodiments, theratio of methane sulfonic acid and Compound II-OH is about 1:1.

In some embodiments, step b) of the synthesis of Compound I-MsOH usescitric acid as the aqueous solution. In other embodiments, step b) ofthe synthesis of Compound I-MsOH further comprises extracting Compound Iand drying the extracted solution with 3 Å molecular sieves.

In some embodiments, pure sample of Compound I-MsOH is used to seed inthe crystallization step d) of the synthesis of Compound I-MsOH. Theseeded crystallization solution of step d), in some embodiments,comprise further steps of stirring at about 0° C. to allowcrystallization, collecting formed crystals, and washing collectedcrystals with chilled ethyl acetate. In one embodiment, the formedcrystals are collected by filtration.

In other embodiments, further purification is required by employing hotrecrystallization after step d). The hot recrystallization of CompoundI-MsOH involves i) dissolving crude crystals of Compound I-MsOH obtainedin step d) in acetonitrile at about 70° C., ii) reducing the temperatureof the mixture of step i) to about 50° C. to about 55° C. over about 1hour, iii) seeding step ii) with Compound I-MsOH, iv) stirring at about50° C. to about 55° C. for about 6 hours, v) reducing the temperature ofthe mixture of step iii to about 20° C., vi) stirring at about 20° C.for about 8 hours, vii) collecting crystals of Compound I-MsOH byfiltration, and viii) washing crystals with cold acetonitrile.

The present disclosure describes8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH), which can be characterized by its purity and bythe amount of impurities. In one embodiment, Compound II-OH comprisesone or more of the following: (a) about ≤0.50% to about ≥0.30% or about≤0.01% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A); (b) about ≤0.50% to about ≥0.30% or about≤0.01% of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B); (c) about ≤0.50% to about ≥0.30% of4,4′-bis(2-butoxyethoxy)biphenyl (Compound VII); and (d) about ≤0.50% toabout ≥0.30% or about ≤0.01% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and optionally further comprises one or both ofabout ≤0.50% of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C); and about ≤0.50% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX).

In one embodiment, Compound II-OH comprises one or both of (a) about≤0.50% to about ≥0.30% of Compound II-OH-A; and (b) about ≤0.50% toabout ≥0.30% of Compound II-OH-B; and optionally further comprises about≤0.50% of Compound II-OH-C. In other embodiments, Compound II-OHcomprises: (a) about ≤0.50% to about ≥0.30% of Compound II-OH-A; (b)about ≤0.50% to about ≥0.30% of Compound II-OH-B; and (c) about ≤0.50%of Compound II-OH-C.

In one embodiment, Compound II-OH comprises one or both of: (a) about≤0.01% of Compound II-OH-A; and (b) about ≤0.01% of Compound II-OH-B;and optionally further comprises about ≤0.10% of Compound II-OH-C. Insome embodiments, Compound II-OH comprises (a) about ≤0.01% of CompoundII-OH-A; (b) about ≤0.01% of Compound II-OH-B; and (c) about ≤0.10% ofCompound II-OH-C.

In one embodiment, Compound II-OH comprises one or both of: (a) about≤0.50% to about ≥0.30% of Compound VII; and (b) about ≤0.50% to about≥0.30% of Compound VIII; and optionally further comprises about ≤0.50%of Compound IX. In other embodiments, Compound II-OH comprises (a) about≤0.50% to about ≥0.30% of Compound VII; (b) about ≤0.50% to about ≥0.30%of Compound VIII; and (c) about ≤0.50% of Compound IX. In someembodiments, Compound II-OH comprises about ≤0.01% of Compound VIII, andoptionally further comprises one or both of (i) about ≤0.05% of CompoundVII, and (ii) about ≤0.15% of Compound IX. In further embodiment,Compound II-OH comprises: (a) about ≤0.05% of Compound VII; (b) about≤0.01% of Compound VIII; and (c) about ≤0.15% of Compound IX.

In one embodiment, Compound II-OH comprises about ≤0.50% to about ≥0.30%of Compound II-OH-A. In some embodiments, Compound II-OH comprises≤0.01% of Compound II-OH-A.

In one embodiment, Compound II-OH comprises about ≤0.50% to about ≥0.30%of Compound II-OH-B. In some embodiments, Compound II-OH comprises≤0.01% of Compound II-OH-B.

In one embodiment, Compound II-OH comprises about ≤0.50% to about ≥0.30%of Compound VII. In one embodiment, Compound II-OH comprises about≤0.50% to about ≥0.30% of Compound VIII. In some embodiments, CompoundII-OH comprises ≤0.01% of Compound VIII.

In some embodiments, Compound II-OH has about ≥95.0% to about ≤96.0%purity. In another embodiment, Compound II-OH has about >97.0% purity.

In some embodiments, Compound II-OH has about ≥95.0% to about ≤96.0%purity and comprises 4,4′-bis(2-butoxyethoxy)biphenyl (Compound VII) in0.20% or less. In some embodiments, Compound II-OH has about ≥95.0% toabout ≤96.0% purity and comprises8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in 0.50% or less. In one embodiment, CompoundII-OH has about ≥95.0% to about ≤96.0% purity and comprises8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in 0.50% or less.

In some embodiments, Compound II-OH has about ≥95.0% to about ≤96.0%purity and comprises 4,4′-bis(2-butoxyethoxy)biphenyl (Compound VII) tin 0.10% or less; or8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in 0.10% or less; or8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in 0.15% or less. In other embodiments, CompoundII-OH has about ≥95.0% to about ≤96.0% purity and comprises one or moreof the following: (a) 0.50% or less of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A); (b) 0.50% or less of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B); (c) 0.50% or less of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C); (d) 0.50% or less of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and/or (e) 0.50% or less of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX).

In one embodiment, Compound II-OH has about ≥95.0% to about ≤96.0%purity and comprises Compound II-OH-A in 0.10% or less. In otherembodiments, Compound II-OH has about ≥95.0% to about ≤96.0% purity andcomprises Compound II-OH-C in 0.10% or less. In some embodiments,Compound II-OH has about ≥95.0% to about ≤96.0% purity and comprisesCompound VIII in 0.10% or less. In a further embodiment, Compound II-OHhas about ≥95.0% to about ≤96.0% purity and comprises Compound IX in0.20% or less.

In other embodiments, Compound II-OH has about ≥95.0% to about ≤96.0%purity and comprises one or more of the following: (a) 0.05% or less of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A); (b) 0.05% or less of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B); (c) 0.05% or less of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C); (d) 0.05% or less of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and/or (e) 0.15% or less of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX).

The present disclosure describes8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(2-(1-propyl-1H-imidazol-5-yl)acetyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH), which can be characterized by itspurity and by the amount of impurities. In one embodiment, CompoundI-MsOH, or an enantiomer, a stereoisomer, or a combination thereof, witha purity of ≥96.0% or ≥98.5% or higher, wherein said compound comprisesone or more of the following: (a) about ≤0.50% to about ≥0.30% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); (b) about ≤0.50% to about ≥0.30% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX); (c) about ≤0.50% to about ≥0.30% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A); (d) about ≤0.50% to about ≥0.30%of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B); (e) about ≤0.50% to about ≥0.45%of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C); (f) about ≤0.50% to about ≥0.45%of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E); (g) about ≤0.50% to about ≥0.45%of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F); and (h) about ≤0.50% to about≥0.45% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G).

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤1.0% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH). In another embodiment, Compound I-MsOH, or anenantiomer, a stereoisomer, or a combination thereof, with a purity of≥96.0% or ≥98.5% or higher comprises 2000 ppm or less of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III).In some embodiments, Compound III is present in 1500 ppm or less.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤2.0% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D). In some embodiment, CompoundI-MsOH-D is present in ≤1.0%.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.10% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII), provided that there is present one or more of:(b) about ≤0.50% to about ≥0.30% of Compound IX; (c) about ≤0.50% toabout ≥0.30% of Compound I-MsOH-A; (d) about ≤0.50% to about ≥0.30% ofCompound I-MsOH-B; (e) about ≤0.50% to about ≥0.45% of CompoundI-MsOH-C; (f) about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; (g)about ≤0.50% to about ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50%to about ≥0.45% of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.10% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX), provided that there is present one or more of: (a)about ≤0.50% to about ≥0.30% of Compound VIII; (c) about ≤0.50% to about≥0.30% of Compound I-MsOH-A; (d) about ≤0.50% to about ≥0.30% ofCompound I-MsOH-B; (e) about ≤0.50% to about ≥0.45% of CompoundI-MsOH-C; (f) about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; (g)about ≤0.50% to about ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50%to about ≥0.45% of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.10% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX), provided that there is present one or more of: (a)about ≤0.50% to about ≥0.30% of Compound VIII; (b) about ≤0.50% to about≥0.30% of Compound IX; (d) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-B; (e) about ≤0.50% to about ≥0.45% of Compound I-MsOH-C; (f)about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; (g) about ≤0.50% toabout ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50% to about ≥0.45%of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.15% of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B), provided that there is present oneor more of: (a) about ≤0.50% to about ≥0.30% of Compound VIII; (b) about≤0.50% to about ≥0.30% of Compound IX; (d) about ≤0.50% to about ≥0.30%of Compound I-MsOH-B; (c) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-A; (e) about ≤0.50% to about ≥0.45% of Compound I-MsOH-C; (f)about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; (g) about ≤0.50% toabout ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50% to about ≥0.45%of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.30% of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C), provided that there is present oneor more of: (a) about ≤0.50% to about ≥0.30% of Compound VIII; (b) about≤0.50% to about ≥0.30% of Compound IX; (d) about ≤0.50% to about ≥0.30%of Compound I-MsOH-B; (c) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-A; (d) about ≤0.50% to about ≥0.30% of Compound I-MsOH-B; (f)about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; (g) about ≤0.50% toabout ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50% to about ≥0.45%of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.30% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E), provided that there is present oneor more of: (a) about ≤0.50% to about ≥0.30% of Compound VIII; (b) about≤0.50% to about ≥0.30% of Compound IX; (d) about ≤0.50% to about ≥0.30%of Compound I-MsOH-B; (c) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-A; (d) about ≤0.50% to about ≥0.30% of Compound I-MsOH-B; (e)about ≤0.50% to about ≥0.45% of Compound I-MsOH-C; (g) about ≤0.50% toabout ≥0.45% of Compound I-MsOH-F; and (h) about ≤0.50% to about ≥0.45%of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.20% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F), provided that there is present oneor more of: (a) about ≤0.50% to about ≥0.30% of Compound VIII; (b) about≤0.50% to about ≥0.30% of Compound IX; (d) about ≤0.50% to about ≥0.30%of Compound I-MsOH-B; (c) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-A; (d) about ≤0.50% to about ≥0.30% of Compound I-MsOH-B; (e)about ≤0.50% to about ≥0.45% of Compound I-MsOH-C; (f) about ≤0.50% toabout ≥0.45% of Compound I-MsOH-E; and (h) about ≤0.50% to about ≥0.45%of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises ≤0.15% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G), provided that there is presentone or more of: (a) about ≤0.50% to about ≥0.30% of Compound VIII; (b)about ≤0.50% to about ≥0.30% of Compound IX; (d) about ≤0.50% to about≥0.30% of Compound I-MsOH-B; (c) about ≤0.50% to about ≥0.30% ofCompound I-MsOH-A; (d) about ≤0.50% to about ≥0.30% of CompoundI-MsOH-B; (e) about ≤0.50% to about ≥0.45% of Compound I-MsOH-C; (f)about ≤0.50% to about ≥0.45% of Compound I-MsOH-E; and (g) about ≤0.50%to about ≥0.45% of Compound I-MsOH-F.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises one or more of the following: (i) ≤0.30% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH); (ii) ≤0.05% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and (iii) ≤0.05% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX), provided there is present one or more of compounds:(c) about ≤0.50% to about ≥0.30% of Compound I-MsOH-A; (d) about ≤0.50%to about ≥0.30% of Compound I-MsOH-B; (e) about ≤0.50% to about ≥0.45%of Compound I-MsOH-C; (f) about ≤0.50% to about ≥0.45% of CompoundI-MsOH-E; (g) about ≤0.50% to about ≥0.45% of Compound I-MsOH-F; and (h)about ≤0.50% to about ≥0.45% of Compound I-MsOH-G.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprises one or more of the following: (i) 1300 ppm or less wherein4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III);(ii) ≤0.10% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A); (iii) ≤0.10% of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B); (iv) ≤0.20% of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C); (v) ≤0.80% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D); (vi) ≤0.20% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E); (vii) ≤0.15% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F); and (viii) ≤0.10% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G), provided there is present one ormore of compounds (a) about ≤0.50% to about ≥0.30% of Compound VIII and(b) about ≤0.50% to about ≥0.30% of Compound IX.

In one embodiment, Compound I-MsOH, or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or highercomprising mesylate ester resulting from MsOH in 0.001% or less, or 10ppm or less.

In one embodiment, Compound I-MsOH as disclosed herein is(S)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((S)-Compound I-MsOH). In some embodiments,(S)-Compound I-MsOH comprises ≤0.5% of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH). In some embodiments,(S)-Compound I-MsOH comprises ≤0.2% of (R)-Compound I-MsOH.

In some embodiments, (S)-Compound I-MsOH comprises 5.0% w/w or less or2.0% w/w or less water content.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. shows a proton NMR (nuclear magnetic resonance spectroscopy)spectrum of (S)-Compound II-OH.

FIG. 2. shows a proton NMR spectra of Compound V-3 (top), Compound V-3with D₂O (middle), and Compound II-OH (bottom).

FIG. 3. shows an expansion of the aromatic region of the NMR spectra ofFIG. 2.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

The term “a” or “an” refers to one or more of that entity; for example,“a halogen” refers to one or more halogens or at least one halogen. Assuch, the terms “a” (or “an”), “one or more” and “at least one” are usedinterchangeably herein. In addition, reference to “an alkyl group” bythe indefinite article “a” or “an” does not exclude the possibility thatmore than one of the alkyl group is present, unless the context clearlyrequires that there is one and only one of the alkyl groups.

As used herein, the verb “comprise” as is used in this description andin the claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded.

As used herein, the phrase “alkyl group” refers to a straight chain, abranched chain or a cyclic hydrocarbons having from 1 up to about 10carbon atoms. Non-limiting examples of an alkyl group includes C1-C10alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,octyl, nonyl, decyl, and the like.

As used herein the phrase “aryl group” refers to an aromatic grouphaving from 6 up to 14 carbon atoms. Non-limiting examples of an arylgroup includes phenyl, naphthyl, anthryl, fluorenyl, and the like.

As used herein, the phrase “substituent(s)” in the optionallysubstituted alkyl group and the optionally substituted aryl groupincludes a halogen atom (e.g., fluorine, chlorine, bromine, iodine,etc.), a nitro group, a cyano group, an optionally substituted hydroxylgroup (e.g., a hydroxyl group, C1-C4 alkoxy, etc.), an optionallysubstituted thiol group (e.g., thiol, C1-C4 alkylthio, etc.), anoptionally substituted amino group (e.g., amino, mono-C1-C4 alkylamino,di-C1-C4 alkylamino, a 5- or 6-membered cyclic amino group such as,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, pyrroleand imidazole, etc.), an optionally esterified or amidated carboxylgroup (e.g., carboxyl, C1-C4 alkoxycarbonyl, carbamoyl, mono-C1-C4alkylcarbamoyl, di-C1-C4 alkylcarbamoyl, etc.), an optionallyhalogenated C1-C4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenatedC1-C4 alkoxy-C1-C4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), aformyl group, a C2-C4 alkanoyl group (e.g., acetyl, propionyl, etc.) anda C1-C4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,etc.).

As used herein, the phrase “short-chain alcohol” refers to alcoholcontaining 1-8 carbon atoms. Non-limiting examples of short-chainalcohol includes methanol, ethanol, propanol, isopropanol, butanol,pentanol, hexanol, heptanol, octanol, and the like.

As used herein, the phrase “nonprotic solvent” or “non-protic solvent”refers to an organic solvent or mixtures of organic solvents that is notreadily deprotonated in the presence of a strongly basic reactant.Non-limiting examples of non-protic solvents include ethers,dimethylformamide (DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide, diethoxymethane,tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycoldimethyl ether, ethylene glycol diethyl ether, diethylene glycoldimethyl ether, diethylene glycol diethyl ether, triethylene glycoldimethyl ether, anisole, t-butyl methyl ether, and the like.

As used herein, the phrase “protic solvent” refers to a solvent orsolvent mixtures that is capable of functioning as an acid for purposesof protonating any unreacted, strongly basic reaction intermediates.Non-limiting examples of protic solvents include water, methanol,ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol,ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol,2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethyleneglycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol,diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,cyclohexanol, benzyl alcohol, phenol, glycerol, and the like.

As used herein, the phrase “part(s)” when used to describe volume of aliquid refers to an approximate estimate of the volume multiplier to acompound, substance, or liquid in which it refers to or which is statedpreviously. For example, 50 parts water with respect to Compound A meanswater with approximately 50 times the volume of Compound A is used.

As used herein, the symbol “≤” means “not more than” or “equal to orless than”; “<” means “less than”; “≥” means “not less than” or “equalto or more than”; and “>” means “more than”. Furthermore, the numericalnumbers, when used herein in connection with purity or impurity content,include not only the exact number but also the approximate range aroundthe number. For example, the phrase “purity of 99.0%” denotes a purityof about 99.0%.

Compounds and Purities/Impurities

The compounds of the disclosure, or their pharmaceutically acceptablesalts can contain one or more asymmetric centers and can thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that canbe defined, in terms of absolute stereochemistry, as (R)- or (S)-. Thepresent disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms whether or not they arespecifically depicted herein. Optically active (+) and (−), or (R)- and(S)-isomers can be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another. In one embodiment, compounds disclosedherein include racemic mixtures, enantiomers, diastereomers, orenantiomerically or diasteriomerically enriched mixtures.

The disclosed process, in some embodiments, for the synthesis ofCompound II-OH provides Compound II-OH in about ≥95.0% to about ≤96.0%purity. In another embodiment, the disclosed process for the synthesisof Compound II-OH provides Compound II-OH in about >97.0% purity. In oneembodiment, the disclosed process for the synthesis of Compound II-OHprovides Compound II-OH in about >97.5% purity. In another embodiment,the disclosed process for the synthesis of Compound II-OH providesCompound II-OH in about >98.0% purity. In some embodiments, thedisclosed process for the synthesis of Compound II-OH provides CompoundII-OH in about >99.0% purity.

In other embodiments, the disclosed synthesis of Compound II-OH resultsin the presence of 4,4′-bis(2-butoxyethoxy)biphenyl (Compound VII) inabout ≤0.50% to about ≥0.30%. In one embodiment, the disclosed synthesisof Compound II-OH results in the presence of Compound VII in about≤0.20%. In one embodiment, the disclosed synthesis of Compound II-OHresults in the presence of Compound VII in about ≤0.10%. In someembodiment, the disclosed synthesis of Compound II-OH results in thepresence of Compound VII in about ≤0.05%.

In other embodiments, the disclosed synthesis of Compound II-OH resultsin the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about >0.20%. In otherembodiments, the disclosed synthesis of Compound II-OH results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about ≥0.25%. In otherembodiments, the disclosed synthesis of Compound II-OH results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about ≥0.30%. In oneembodiment, the disclosed synthesis of Compound II-OH results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.20%. In other embodiments, thedisclosed synthesis of Compound II-OH results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.10%. In one embodiment, the disclosedsynthesis of Compound II-OH results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.05%. In some embodiments, thedisclosed synthesis of Compound II-OH results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.01%.

In other embodiments, the disclosed synthesis of Compound II-OH resultsin the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.50%. In another embodiment, the disclosedsynthesis of Compound II-OH results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.25%. In one embodiment, the disclosedsynthesis of Compound II-OH results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.15%. In one embodiment, the disclosedsynthesis of Compound II-OH results in the presence of Compound IX inabout ≤0.10%. In one embodiment, the disclosed synthesis of CompoundII-OH results in the presence of Compound IX in about ≤0.05%.

In some embodiments, the disclosed synthesis of Compound II-OH result inthe presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.50% to about >0.20%. In someembodiments, the disclosed synthesis of Compound II-OH result in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.50% to about ≥0.25%. In someembodiments, the disclosed synthesis of Compound II-OH result in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.50% to about ≥0.30%. In oneembodiment, the disclosed synthesis of Compound II-OH results in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.20%. In other embodiments, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.10%. In one embodiment, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.05%. In another embodiment, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A) in about ≤0.01%.

In some embodiments, the disclosed synthesis of Compound II-OH resultsin the presence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.50% to about ≥0.20%. In someembodiments, the disclosed synthesis of Compound II-OH results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.50% to about ≥0.25%. In someembodiments, the disclosed synthesis of Compound II-OH results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.50% to about ≥0.30%. In oneembodiment, the disclosed synthesis of Compound II-OH results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.20%. In one embodiment, thedisclosed synthesis of Compound II-OH results in the presence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.10%. In one embodiment, thedisclosed synthesis of Compound II-OH results in the presence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.05%. In another embodiment, thedisclosed synthesis of Compound II-OH results in the presence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B) in about ≤0.01%.

In one embodiment, the disclosed synthesis of Compound II-OH results inthe presence of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C) in about ≤0.50%. In some embodiments, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C) in about ≤0.25%. In one embodiment, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C) in about ≤0.15%. In other embodiments, thedisclosed synthesis of Compound II-OH results in the presence of8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-C) in about ≤0.10%. In other embodiments, thedisclosed synthesis of Compound II-OH results in the presence ofCompound II-OH-C in about ≤0.05%.

In other embodiments, the disclosed synthesis of Compound II-OH resultsin the presence of Compound II-OH-C in about ≤0.01%.

In one embodiment, the disclosed synthesis of Compound II-OH results inthe presence of one or more of the following:

(a) about ≤0.50% to about ≥0.30% or about ≤0.01% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-A);

(b) about ≤0.50% to about ≥0.30% or about ≤0.01% of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH-B);

(c) about ≤0.50% to about ≥0.30% of 4,4′-bis(2-butoxyethoxy)biphenyl(Compound VII); and

(d) about ≤0.50% to about ≥0.30% or about ≤0.01% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and optionally further comprises one or both of

-   -   (i) about ≤0.50% of        8-(4-butoxyphenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic        acid (Compound II-OH-C); and    -   (ii) about ≤0.50% of        8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic        acid (Compound IX).

The disclosed process, in some embodiments, the synthesis of CompoundI-MsOH provides Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, in about ≥95.0% to about ≤95.5% purity. In oneembodiment, the disclosed process for the synthesis of Compound I-MsOHprovides Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, in about >96.0% purity. In another embodiment, thedisclosed process for the synthesis of Compound I-MsOH provides CompoundI-MsOH or an enantiomer, a stereoisomer, or a combination thereof, inabout >97.0% purity. In one embodiment, the disclosed process for thesynthesis of Compound I-MsOH provides Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, in about >98.0% purity. Insome embodiments, the disclosed process for the synthesis of CompoundI-MsOH provides Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, in about >98.5% purity.

In other embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH) in about ≤1.0%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH) in about ≤0.80% or about ≤0.50%. In someembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH) in about ≤0.25%.

In other embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about ≥0.20%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about ≥0.25%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.50% to about ≥0.30%. In someembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.20%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.10%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.05%. In another embodiment, thedisclosed synthesis of Compound I-MsOH or an enantiomer, a stereoisomer,or a combination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) in about ≤0.01%.

In other embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.50% to about ≥0.20%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.50% to about ≥0.25%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.50% to about ≥0.30%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.25%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.20%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.15%. In one embodiment, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.10%. In some embodiments, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) in about ≤0.05%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline(Compound III) or an enantiomer, a stereoisomer, or a combinationthereof, in about ≤0.50% to about ≥0.35%. In one embodiment, thedisclosed synthesis of Compound I-MsOH or an enantiomer, a stereoisomer,or a combination thereof, results in the presence of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) oran enantiomer, a stereoisomer, or a combination thereof, in about≤0.25%. In one embodiment, the disclosed synthesis of Compound I-MsOH oran enantiomer, a stereoisomer, or a combination thereof, results in thepresence of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline(Compound III) or an enantiomer, a stereoisomer, or a combinationthereof, in about ≤0.15%. In another embodiment, the disclosed synthesisof Compound I-MsOH or an enantiomer, a stereoisomer, or a combinationthereof, results in the presence of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) oran enantiomer, a stereoisomer, or a combination thereof, in about≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline(Compound III) or an enantiomer, a stereoisomer, or a combinationthereof, in about ≤2000 ppm. In some embodiments, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) oran enantiomer, a stereoisomer, or a combination thereof, in about ≤1750ppm. In some embodiments, the disclosed synthesis of Compound I-MsOH oran enantiomer, a stereoisomer, or a combination thereof, results in thepresence of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline(Compound III) or an enantiomer, a stereoisomer, or a combinationthereof, in about ≤1500 ppm. In some embodiments, the disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) oran enantiomer, a stereoisomer, or a combination thereof, in about ≤1250ppm.

In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of (S)-4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline((S)-Compound III) in about ≤1500 ppm.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A) in about ≤0.50% to about ≥0.25%. Insome embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A) in about ≤0.50% to about ≥0.30%. Inone embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A) in about ≤0.25%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A) in about ≤0.15%. In anotherembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A) in about ≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B) in about ≤0.50% to about >0.25%. Insome embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B) in about ≤0.50% to about ≥0.30%. Inone embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B) in about ≤0.25%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B) in about ≤0.15%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B) in about ≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.50% to about >0.40%. Insome embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.50% to about ≥0.45%. Inone embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.40%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.30%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.20%. In anotherembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C) in about ≤0.10%.

In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D) in about ≤2.0%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D) in about ≤1.0%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D) in about ≤0.50%. In anotherembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D) in about ≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.50% to about >0.40%. Insome embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.50% to about ≥0.45%. Inone embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.40%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.30%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.20%. In anotherembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E) in about ≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.50% to about >0.40%. Insome embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.50% to about ≥0.45%. Inone embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.40%. In otherembodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.30%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.20%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.15%. In one embodiment,the disclosed synthesis of Compound I-MsOH or an enantiomer, astereoisomer, or a combination thereof, results in the presence of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F) in about ≤0.10%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.50% to about >0.40%.In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.50% to about ≥0.45%.In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.50% to about ≥0.30%.In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.40%. In oneembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.30%. In oneembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.20%. In oneembodiment, the disclosed synthesis of Compound I-MsOH or an enantiomer,a stereoisomer, or a combination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.15%. The disclosedsynthesis of Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof, results in the presence of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G) in about ≤0.10%.

In another embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or combinations thereof, results in thepresence of mesylate esters, resulting from MsOH, in about ≤1.0%. Inother embodiments, the disclosed synthesis of Compound I-MsOH results inthe presence of mesylate esters, resulting from MsOH, in about ≤0.50%.In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or combinations thereof, results in thepresence of mesylate esters, resulting from MsOH, in about ≤0.25%.

In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or combinations thereof, results in thepresence of mesylate esters, resulting from MsOH, in about ≤20 ppm. Inother embodiments, the disclosed synthesis of Compound I-MsOH results inthe presence of mesylate esters, resulting from MsOH, in about ≤10 ppm.In one embodiment, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or combinations thereof, results in thepresence of mesylate esters, resulting from MsOH, in about ≤5 ppm. Insome embodiments, Compound I-MsOH or an enantiomer, a stereoisomer, or acombination thereof contains 10 ppm mesylate ester for a 150 mg dose.

In one embodiment, the disclosed synthesis of Compound I-MsOH results in(S)-Compound I-MsOH. In some embodiments, the disclosed synthesisprovides (S)-Compound I-MsOH in greater than 96% purity or greater than98.5% purity.

In some embodiments, the disclosed synthesis of (S)-Compound I-MsOHresults in the presence of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH) in about ≤1.00%. In anotherembodiment, the disclosed synthesis of (S)-Compound I-MsOH results inthe presence of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH) in about ≤0.50%. In oneembodiment, the disclosed synthesis of (S)-Compound I-MsOH results inthe presence of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH) in about ≤0.25%.

In some embodiments, the disclosed synthesis of Compound I-MsOH or anenantiomer, a stereoisomer, or a combination thereof, results in thepresence of 5.0% w/w or less or 2.0% w/w or less water content.

In some embodiments, the disclosed synthesis of (S)-Compound I-MsOHresults in the presence of ≤3.0% impurity including (R)-Compound I-MsOHbut excluding (S)-Compound III. In one embodiment, the disclosedsynthesis of (S)-Compound I-MsOH results in the presence of ≤2.5%impurity including (R)-Compound I-MsOH but excluding (S)-Compound III.In another embodiment, the disclosed synthesis of (S)-Compound I-MsOHresults in the presence of ≤2.3% impurity including (R)-Compound I-MsOHbut excluding (S)-Compound III. In some embodiments, the disclosedsynthesis of (S)-Compound I-MsOH results in the presence of ≤2.0%impurity including (R)-Compound I-MsOH but excluding (S)-Compound III.

Process for the Synthesis of Compound V

Compound V, in some embodiments, represents boronic acids, boronicesters, pinacolboranes, boronic acid dimers, boronic acid trimers,mixtures thereof, or the like. It is commonly understood in the art thatCompound V can be presented as various derivatives of boronic acids.

In some embodiments, dimethyl (4-(2-butoxyethoxy)phenyl)boronate(Compound V-OMe) is prepared by a Grignard formation of1-bromo-4-(2-butoxyethoxy)benzene (Compound VI) and a subsequentreaction with trimethoxyborane.

It was discovered in a large scale batch that Grignard initiation wasdifficult. The previous process employed a dilute solution of CompoundVI, approximately 50-70 parts tetrahydrofuran (THF) with respect toCompound VI. The initiation was very slow in the dilute solution ofCompound VI with isopropylmagnesium chloride (iPrMgCl), which onlyoccurred after prolonged reflux and addition of increased amounts ofCompound VI, bringing the concentration to approximately 25 parts THFwith respect to Compound VI. In addition to the difficulties ininitiating the Grignard, it was found that the use of iPrMgCl had anadverse effect in the subsequent step (lower conversion of the Suzukicoupling step; see section Process for the synthesis of Compound II-OH).

To overcome the Grignard initiation issues, the activation step of themagnesium turnings, by heating and agitation, prior to the Grignardformation is necessary. In some embodiments, magnesium turnings werestirred for about 1 hour in about 9 parts of an ethereal solvent, suchas THF. Subsequently, the solvent can be reduced to about 3 parts bydistillation.

The Grignard initiation challenges, in some embodiments, are solved byusing neat Compound VI to provide a more concentrated solution than theprevious methods. In some embodiments, approximately 20% of the totalamount of Compound VI is added neat to the solution of activatedmagnesium turnings over a period of at least 15 minutes, while theexotherm is controlled, such that the temperature of the reaction ismaintained below the boiling point of the solvent. The resultingsolution is heated at or around the boiling point of the solvent forabout 1 hours to about 4 hours. The reaction mixture is then cooled byabout 10° C. and diluted with the same solvent as used previously (5parts). This disclosed Grignard initiation step, in some embodiments,results in the complete omission of iPrMgCl.

To the hot initiated Grignard solution, which is further diluted, theremaining Compound VI is slowly added neat over a period of about 30minutes to about 1 hour. The addition of Compound VI is exothermic andthe reaction mixture is carefully maintained to be well below theboiling point during the addition. The resulting mixture is stirred andheated to temperature below the boiling point of the solvent, forexample about 55° C. for THF, for about 3 hours to about 4 hours. Theheating time can be extended until high-performance liquidchromatography (HPLC) analysis indicates less than about 1% of CompoundVI is remaining. It was noted that prolong heating time had nobeneficial effect on the yield of the subsequent step or in theprevention of key impurity formations.

Previous process route for the synthesis of Compound V-OMe involvedcooling the Grignard mixture to about −15° C. and adding a solution oftrimethoxyborane in THF. The inventors discovered that this temperaturerange was not optimal and lead to lower yields and higher impurities.Also, it was found that the reaction was sensitive to the rate ofaddition of trimethoxyborane.

Considering the above findings, in some embodiments, Grignard mixture(once formation is complete) is cooled to about −25° C. and neattrimethoxyborane is added portion-wise over about 2 hours. The reactionmixture was stirred at about −25° C. for about 1 hour to about 2 hoursupon completion of the trimethoxyborane addition, then warmed up toabout 20° C. and stirred for about 1 hour to about 2 hours to provideCompound V-OMe. In some embodiments, the neat trimethoxyborane waschilled prior to the addition to the Grignard mixture.

In some embodiments, the ratio of magnesium turning, Compound VI, andtrimethoxyborane is about 1.08:1:1.

In some embodiments, anhydrous solvents are used in the synthesis ofCompound V. In other embodiments, the reaction for the synthesis ofCompound V is maintained under atmospheric pressure of nitrogen or argonand the reaction vessels and equipment are rid of moisture prior to use.

In some embodiments, Compound VI and trimethoxyborane is both used as aneat solution to minimize reactor usage.

It was noted that filtration of the crude Compound V-OMe to removeexcess magnesium and magnesium salts is not necessary as it had noeffect on the subsequent step in terms of preventing key impurityformation.

Preparation of Compound V-OH

In some embodiments, Compound V is Compound V-OH. In one embodiment,Compound V-OH is synthesized by process known to one skilled in the art.In one embodiment, commercially available Compound V-OH (CAS No.279262-28-1) is purified to obtain a crystalline Compound V-OH which isessentially free of Compounds V-A, V-B, and V-C.

In one embodiment, Compound V is Compound V-OH with ≤0.10% of CompoundV-OH-A, Compound V-OH-B and/or Compound V-OH-C.

In some embodiments, Compound V-OH is dried such that the loss on drying(LOD) is below about 20%, about 19%, about 18%, about 17%, about 16%,about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about9%, about 8%, about 7%, about 6%, or about 5%. In one embodiment,Compound V-OH is dried such that the loss on drying (LOD) is about 15%,about 14%, about 13%, about 12%, about 11%, or about 10%. In someembodiment, prolonged drying of Compound V-OH results in the formationof Compound V-3.

In one embodiment, Compound V-OH is about ≥85%, about ≥90%, about ≥95%,about ≥96%, about ≥97%, about ≥98%, or about ≥99% pure.

In other embodiments, dried sample of Compound V-OH can contain CompoundV-3 in about 30%, about 29%, about 28%, about 27%, about 26%, about 25%,about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%,about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%,about 4%, about 3%, about 2%, or about 1%. In one embodiment, isolatedcrystalline Compound V-OH comprises Compound V-3 in less than about 5%,about 4%, about 3%, about 2%, about 1%, or about 0.5%.

In one embodiment, Compound V-3 is about ≥85%, about ≥90%, about ≥95%,about ≥96%, about ≥97%, about ≥98%, or about ≥99% pure.

In one embodiment, a mixture of dried Compound V-OH and Compound V-3 canbe used in the reaction with Compound IV. In some embodiments, mixtureof Compound V-OH and Compound V-3 can be in the ratio of about 1:99 toabout 99:1. In other embodiments, the ratio of Compound V-OH andCompound V-3 can be about 5:95 to about 95:5. In one embodiment, themixture of dried Compound V-OH and Compound V-3 is essentially free ofCompounds V-A, V-B, and V-C. In other embodiments, the mixture of driedCompound V-OH and Compound V-3 comprises ≤0.10% of Compound V-OH-A,Compound V-OH-B and/or Compound V-OH-C.

In one embodiment, the mixture of Compound V-OH and Compound V-3 isabout ≥85%, about ≥90%, about ≥95%, about ≥96%, about ≥97%, about ≥98%,or about ≥99% pure.

Process for the Synthesis of Compound II-OH

In some embodiments, Compound II-OH is prepared by the reaction betweenCompound IV and Compound V. In other embodiments, Compound II-OH isprepared by a transition metal-catalyzed process, such as a Suzukicoupling reaction, between Compound IV and Compound V. In oneembodiment, the amount of Compound V used is about 1 equivalent (equiv)to about 3 equiv with respect to Compound IV. In other embodiments, theamount of Compound V used is about 2 equiv with respect to Compound IV.

A previous process for the synthesis of Compound II-OH also involved aSuzuki coupling reaction where the reaction mixture containing CompoundV was charged with palladium acetate (Pd(OAc)₂) catalyst andtriphenylphosphine ligand (PPh₃), prior to the addition of aqueous basesolution (water and solid base). This synthetic route yielded CompoundII-OH in a moderate yield of about 55% to about 64% yield with purityranging from about 92% to about 99%.

It was discovered that, in some embodiments, the addition of the aqueousbase solution to form a biphasic mixture prior to the addition of thepalladium (Pd) catalyst and the ligand is beneficial in reducingCompound VII impurity, resulting from homo-coupling of Compound V. Insome embodiments, a solution of a base in about 6.5 parts water is addedto the reaction mixture containing Compound V, prepared as describedpreviously. In other embodiments, base may be selected from the groupconsisting of alkali carbonates (potassium carbonate, sodium carbonate,cesium carbonate, etc), alkali metal hydrogen carbonates (potassiumbicarbonate, sodium bicarbonate, etc), alkaline metal acetates(potassium acetate, sodium acetate, etc), alkaline metal phosphates(potassium phosphate, sodium phosphate, etc), alkali metal fluorides(potassium fluoride, cesium fluoride, etc), alkaline metal alkoxides(potassium tert-butoxide, sodium tert-butoxide, etc), alkali metalhydroxides (potassium hydroxide, sodium hydroxide, etc), and organicbases such as alkyl amines (triethylamine, diisopropylamine,diisopropylethyl amine, etc) pyridines (pyridine, dimethylaminopyridine,etc), cyclic amines (morpholine, 4-methylmorpholine, etc), and thecombination thereof. In one embodiment, the base is potassium carbonate(K₂CO₃). In some embodiments, the equivalent of base is about 1 equiv toabout 8 equiv with respect to Compound IV.

The addition of the aqueous base solution, in some embodiments, iscarried out over a period of at least 30 minutes to at least 1 hour. Theslow addition of the base solution was found critical in the yield ofthe Suzuki coupling reaction. Without being bound to any theory, this ispresumably due to the prevention of salt formation during the biphasicmixture formation.

Previous synthetic routes of the Suzuki coupling reaction raised issuesregarding reaction conversion when carried out in a large scale. It wasdiscovered that purging the biphasic reaction mixture with nitrogen(N₂), by bubbling N₂ directly into the reaction mixture, for about 1hour to rid air content, such as oxygen, provided the desired reactionconversion. This process is known as the degassing. Degassing thereaction mixture was also found beneficial in reducing Compound VIIimpurities from the Suzuki coupling step.

In some embodiments, to a degassed biphasic reaction mixture containingCompound V, a Pd-catalyst and a ligand is added. Previous syntheticroute utilized tetrakis(triphenylphosphine) palladium (Pd(PPh₃)₄)catalyst system achieved by adding Pd(OAc)₂ and PPh₃. The yield of theSuzuki reaction using Pd(PPh₃)₄ catalyst system was not optimal asrepresented by the moderate yield of Compound II-OH (about 55% to about64% yield).

Further optimization of the catalyst system was undertaken to improveyields and to lower Compound VIII impurity. As described in Example 1and Table 1, optimization of the Pd(PPh₃)₄ catalyst system demonstratedthat good conversion was achieved only when catalyst loading wassignificantly increased (from about 2 mol % to about 10 mol %, Table 1entry 6) or when the reaction was refluxed substantially longer time(about 27 hours, entry 5). It was also noted that when high catalystloading was employed, the amount of Compound VIII impurity wassignificantly lower (0.04%, entry 6); however, high catalyst loadinginterfered with the crystallization of the product. Also, lowering thetemperature for the Suzuki coupling reaction showed unsuccessful inpreventing Compound VIII impurity.

Next, different catalyst systems were considered as shown in Example 2and Table 2. Removal of the phosphine ligands (Table 2, entry 1) wasshown detrimental to the reaction conversion. The inventors discoveredthat catalyst system of Pd(OAc)₂/P(o-tol)₃ increased reaction yield(about 80-85%) and product purity (≥99%) compared to the previousPd(PPh₃)₄ catalyst system. Furthermore, with the newly discoveredPd(OAc)₂/P(o-tol)₃ catalyst system, the catalyst loading could beminimized significantly from about 2 mol % to about 0.25 mol %. It wasalso noted that with the disclosed catalyst system, degassing thereaction did not affect conversion rate, purity of the product, or theamount of Compound VIII. The catalyst optimization study from Examples1-2 both indicate the amount of Compound VIII impurity has very littleto no correlation with the Suzuki coupling reaction conditions.

In some embodiments, Pd-catalyst and ligands are added to the reactionbiphasic reaction mixture containing Compound V. In some embodiments,Pd-catalyst can be a Pd(0) species or a Pd(II) species. Non-limitingexamples of Pd-catalyst include tetrakis(triphenylphosphine) palladium(Pd(PPh₃)₄), tri(dibenzylideneacetone) dipalladium,bis(tri-t-butylphosphine) palladium,bis[1,2-bis(diphenylphophino)ethane] palladium,bis(tricyclohexylphosphine) palladium, palladium acetate (Pd(OAc)₂),palladium chloride (PdCl₂), dichlorobis(triphenylphosphine) palladium,palladium acetylacetonate, palladium bromide, palladium iodide,palladium cyanide, palladium hydroxide, palladium nitrate, tetraamminepalladium(II) chloride hydrate, dinitrodiammine palladium,di-g-chlorobis(r-allyl) palladium, dichlorobis(benzonitrile) palladium,dichlorobis(acetonitrile) palladium, palladium propionate,[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride,tetrakis(tri-o-tolylphosphine) palladium, tetrakis(tri-t-butylphosphine)palladium, bis(1,2-bis(diphenylphosphino)ethane) palladium,bis(1,1′-bis(diphenylphosphino)ferrocene) palladium,tetrakis(triethylphosphite) palladium, and combinations thereof.

In some embodiments, the ligand is selected from the group consisting ofphosphine ligands (tritolylphosphine, triphenylphosphine,trimethylphosphine, triethylphosphine, trimethylphosphite,triethylphosphite, tri-n-butylphosphite, tri-tert-butylphosphine,di-tert-butylmethylphosphine, etc), nitrogen based ligands (pyridine,bipyridine, etc), NHC ligands(N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene etc), andcombinations thereof.

In some embodiments, the Pd-catalyst/ligand system isPd(OAc)₂/P(o-tol)₃. In other embodiments, the Pd-catalyst and the ligandare added with continuous degassing of the reaction mixture.

In some embodiments, the amount of Pd-catalyst used is about 0.001 mol %to about 10.0 mol % with respect to Compound IV. In one embodiment, theamount of Pd-catalyst used is about 0.05 mol % to about 0.25 mol % withrespect to Compound IV.

In some embodiments, the ratio of the ligand to the Pd-catalyst is about1:1 to about 3:1. In some embodiments, the ratio of the ligand to thePd-catalyst is about 2:1.

In some embodiments, Compound IV is added to the biphasic mixturecontaining Compound V and Pd-catalyst/ligand system. In one embodiment,Compound IV is added with continuous degassing of the reaction mixture.

In some embodiments, the reaction mixture upon the addition of CompoundIV is heated for about 2 hours to about 5 hours and then cooled toambient temperature. In some embodiments, the reaction mixture is heatedto no greater than 65° C. It was noted that Pd-catalyst becomes inactivewhen temperature is raised above 65° C. For example, a Suzuki reactionset at a temperature of 90° C. did not go to completion. In oneembodiment, the reaction was heated until HPLC analysis indicates ≤2%Compound IV remaining and indicates formation of Compound II-OH.

Once the reaction was deemed complete by HPLC, in some embodiments, thereaction is cooled to ambient temperature and the pH of the reactionmixture was adjusted to about 2.0 to about 3.0 using aqueous acidsolutions. In some embodiment, hydrochloric acid (HCl) is used.

In some embodiments, Compound V is Compound V-OMe.

In some embodiments, Compound V is Compound V-OH. In one embodiment,commercially available Compound V-OH (CAS No. 279262-28-1) is purifiedto obtain a crystalline Compound V-OH which is essentially free ofCompounds V-A, V-B, and V-C.

In one embodiment, Compound V is Compound V-OH with ≤0.10% of CompoundV-OH-A, Compound V-OH-B and/or Compound V-OH-C. In one embodiment,Compound V-OH comprises one or both of: (a) about ≤0.01% of CompoundII-OH-A; and (b) about ≤0.01% of Compound II-OH-B; and optionallyfurther comprises about ≤0.10% of Compound II-OH-C. In anotherembodiment, Compound V-OH comprises (a) about ≤0.01% of CompoundII-OH-A; (b) about ≤0.01% of Compound II-OH-B; and (c) about ≤0.10% ofCompound II-OH-C.

In one embodiment, isolated Compound V-OH is crystalline.

In one embodiment, Compound V-OH comprises less than about 15%, lessthan about 10%, or less than about 5% Compound V-3.

In one embodiment, Compound V-3 is used instead of Compound V-OMe orCompound V-OH. In another embodiment, Compound V-3 is used as a mixtureof Compound V-OH. In one embodiment, Compound V-3 is essentially free ofCompounds V-A, V-B, and V-C. In other embodiment, Compound V-3 comprises≤0.10% of Compound V-OH-A, Compound V-OH-B and/or Compound V-OH-C. Inone embodiment, Compound V-3 comprises one or both of: (a) about ≤0.01%of Compound II-OH-A; and (b) about ≤0.01% of Compound II-OH-B; andoptionally further comprises about ≤0.10% of Compound II-OH-C.

In another embodiment, Compound V-3 comprises (a) about ≤0.01% ofCompound II-OH-A; (b) about ≤0.01% of Compound II-OH-B; and (c) about≤0.10% of Compound II-OH-C.

In one embodiment, dried Compound V-3 comprises less than about 25%,less than about 20%, less than about 15%, less than about 10%, or lessthan about 5% Compound V-OH.

In one embodiment, isolated Compound V-3 is crystalline.

Purification of Compound II-OH

Previous purification process for Compound II-OH required two hotrecrystallizations and two charcoal treatments. The disclosedpurification process, in some embodiments, requires one charcoaltreatment, one anti-solvent recrystallization, and/or one hotrecrystallization.

In one embodiment the improvement in purity of Compound II-OH fromprevious synthesis methods which led to reduction number of steps forpurification of Compound II-OH is attributed to the use of isolatedCompound V-OH and/or Compound V-3 in the reaction with Compound IV. Inone embodiment, the improvement in purity of Compound II-OH fromprevious synthesis methods which led to reduction of number of steps forpurification of Compound II-OH is attributed to the use of crystalline,isolated Compound V-OH and/or Compound V-3 in the reaction with CompoundIV. In a further embodiment, the isolated Compound V-OH and/or CompoundV-3 or the crystalline, isolated Compound V-OH and/or Compound V-3 isessentially free of Compounds V-A, V-B, and V-C.

In one embodiment, the improvement in purity of compound II-OH fromprevious synthesis methods which led to reduction number of steps forpurification of Compound II-OH is attributed to the use of isolatedCompound V-OH in the reaction with Compound IV.

The acidified biphasic reaction mixture containing crude Compound II-OHis, in some embodiments, separated into an aqueous layer and an organiclayer. In some embodiments, the resulting aqueous layer is extractedwith an organic solvent. In one embodiment, the aqueous layer isextracted with toluene (about 10 parts).

The volume of the combined organic layers is, in some embodiments,reduced to about 6.5 parts. In some embodiments, the volume of thecombined organic layer is reduced by distillation. The resulting reducedorganic layer is, in some embodiments, treated with charcoal. In otherembodiments, the resulting reduced organic layer is treated withcharcoal and Celite®. In one embodiment, the ratio of charcoal toCelite® is about 1:2 by weight. The reaction mixture containing charcoalis, in some embodiment, stirred for about 1 hour to about 5 hours at anambient temperature. The charcoal is then, in other embodiments,filtered and the volume of the reaction is reduced to about 3 parts. Inone embodiment, the volume is reduced by distillation.

In some embodiments, antisolvent recrystallization is used forpurification of Compound II-OH. To the reduced crude mixture, polarsolvents, such as isopropanol and ethyl acetate, is added andconcentrated to an oil. In one embodiment, a non-polar antisolvent isadded over a period of about 1 hour, portion wise, to the crude oilmixture. The resulting suspension was stirred at ambient temperature forabout 1 hour to about 8 hours. In some embodiments, the precipitatedcrystals are then collected by filtration. In some embodiments, themother liquor is not recirculated to remove any remaining crystals fromthe reaction vessels; instead multiple solvent wash may be added usingfresh solvents.

In some embodiments, the antisolvent is heptanes. In other embodiments,the polar solvent is isopropanol or a mixture of isopropanol and ethylacetate. In some embodiments, the product precipitates without theaddition of the antisolvent.

In some embodiments, a hot recrystallization is used for purification ofCompound II-OH. The crude material containing Compound II-OH or crudecrystals of Compound II-OH are dissolved in polar solvents such asisopropanol and ethyl acetate at an elevated temperature. Thetemperature of the solution is slowly reduced to ambient temperature andstirred until recrystallization is complete and then the crystals arecollected by filtration.

In some embodiments, the polar solvent used is isopropanol orisopropanol and ethyl acetate mixture. In some embodiments, the crudeCompound II-OH is dissolved in mixture of isopropanol and ethyl acetatein about 9:1 ratio at about 70° C. In other embodiments, the temperatureof the hot solution is decreased by about 10° C. every about 1 houruntil it reaches ambient temperature. In some embodiments, once thesolvent is cooled to an ambient temperature, the solution is stirred forabout 2 hours to about 6 hours. The resulting crystals are, in someembodiments, collected by filtration. In some embodiments, the motherliquor is not recirculated to remove any remaining crystals from thereaction vessels; instead multiple solvent wash may be added using freshsolvents.

Recrystallization solvent study revealed that when hot recrystallizationis carried out in isopropanol alone, the recovery of Compound II-OH washigh (90-93%) and decreased impurity Compound VIII by about 50-60%. Whenhot recrystallization is carried out in ethyl acetate alone, therecovery of Compound II-OH was lower (70-75%) than isopropanol systembut the reduction in impurity Compound VIII was greater (by 80-83%).When hot recrystallization is carried out in a mixture of isopropanoland ethyl acetate, both high recovery of Compound II-OH (90-92%) andeffective reduction in impurity Compound VIII (by 75-80%) was obtained.

In some embodiments, both antisolvent recrystallization and hotrecrystallization is utilized. In some embodiments, the combination ofantisolvent recrystallization and hot recrystallization reduces impurityCompounds VIII and IX significantly. In some embodiments,recrystallization steps can be repeated to reach the desired purity. Inone embodiment, following the disclosed process for the synthesis ofCompound II-OH as described herein, the purity of Compound II-OH isabout ≥95.0% to about ≤96.0% or >97.0%, with one or both of about ≤0.50%to about ≥0.30% of Compound VII, and about ≤0.50% to about ≥0.30% ofCompound VIII, and optionally further comprises about ≤0.50% of CompoundIX. In one embodiment, following the disclosed process for the synthesisof Compound II-OH as described herein, the purity of Compound II-OH isabout ≥95.0% to about ≤96.0% or >97.0%, with about ≤0.50% to about≥0.30% of Compound VII, with about ≤0.50% to about ≥0.30% of CompoundVIII, and with about ≤0.50% of Compound IX. In other embodiments,following the disclosed process for the synthesis of Compound II-OH asdescribed herein, the purity of Compound II-OH is about ≥95.0% to about≤96.0%, with about ≤0.20% of Compound VII, with about ≤0.20% of CompoundVIII, and with about ≤0.50% of Compound IX. In some embodiments,following the disclosed process for the synthesis of Compound II-OH asdescribed herein, the purity of Compound II-OH is about ≥95.0% to about≤96.0%, with about ≤0.10% of Compound VII, with about ≤0.10% of CompoundVIII, and with about ≤0.25% of Compound IX. In one embodiment, followingthe disclosed process for the synthesis of Compound II-OH as describedherein, the purity of Compound II-OH is about ≥95.0% to about ≤96.0%,with about ≤0.05% of Compound VII, with about ≤0.05% of Compound VIII,and with about ≤0.15% of Compound IX. In one embodiment, following thedisclosed process for the synthesis of Compound II-OH as describedherein, the purity of Compound II-OH is about ≥95.0% to about ≤96.0%or >97.0%, with about ≤0.01% of Compound VIII, and optionally furthercomprises one or both of about ≤0.05% of Compound VII, and about ≤0.15%of Compound IX. In one embodiment, following the disclosed process forthe synthesis of Compound II-OH as described herein, the purity ofCompound II-OH is about ≥95.0% to about ≤96.0% or >97.0%, with about≤0.05% of Compound VII, with about ≤0.01% of Compound VIII, and withabout ≤0.15% of Compound IX.

In one embodiment, following the disclosed process for the synthesis ofCompound II-OH as described herein, the purity of Compound II-OH isabout ≥95.0% to about ≤96.0% or >97.0%, with one or both of about ≤0.50%to about ≥0.30% of Compound II-OH-A, and about ≤0.50% to about ≥0.30% ofCompound II-OH-B, and optionally further comprises about ≤0.50% ofCompound II-OH-C. In one embodiment, following the disclosed process forthe synthesis of Compound II-OH as described herein, the purity ofCompound II-OH is about ≥95.0% to about ≤96.0% or >97.0%, with about≤0.50% to about ≥0.30% of Compound II-OH-A, with about ≤0.50% to about≥0.30% of Compound II-OH-B, and with about ≤0.50% of Compound II-OH-C.In one embodiment, following the disclosed process for the synthesis ofCompound II-OH as described herein, the purity of Compound II-OH isabout ≥95.0% to about ≤96.0%, with about ≤0.20% of Compound II-OH-A,with about ≤0.20% of Compound II-OH-B, and with about ≤0.50% of CompoundII-OH-C. In another embodiment, following the disclosed process for thesynthesis of Compound II-OH as described herein, the purity of CompoundII-OH is about ≥95.0% to about ≤96.0%, with about ≤0.10% of CompoundII-OH-A, with about ≤0.10% of Compound II-OH-B, and with about ≤0.25% ofCompound II-OH-C. In some embodiments, following the disclosed processfor the synthesis of Compound II-OH as described herein, the purity ofCompound II-OH is about ≥95.0% to about ≤96.0%, with about ≤0.05% ofCompound II-OH-A, with about ≤0.05% of Compound II-OH-B, and with about≤0.15% of Compound II-OH-C. In some embodiments, following the disclosedprocess for the synthesis of Compound II-OH as described herein, thepurity of Compound II-OH is about ≥95.0% to about ≤96.0% or >97.0%, withone or both of about ≤0.01% of Compound II-OH-A, and about ≤0.01% ofCompound II-OH-B, and optionally further comprises about ≤0.10% ofCompound II-OH-C. In some embodiments, following the disclosed processfor the synthesis of Compound II-OH as described herein, the purity ofCompound II-OH is about ≥95.0% to about ≤96.0% or >97.0%, with about≤0.01% of Compound II-OH-A, with about ≤0.01% of Compound II-OH-B, andwith about ≤0.10% of Compound II-OH-C.

Preparation of Compound I

The previous process for preparing Compound I and subsequently CompoundI-MsOH presented challenges with the presence of Compound II-OH(starting material) in the final product. It was discovered that theformation of Compound II-OH is dependent on several steps or features ofthe reaction. First, the formation of acid chloride Compound II-Cl(Compound II where R₁═Cl). Second, the solvent choice of the reactionaffected the amount of Compound II-OH produced. Third, is regarding thesalt formation step. The disclosed process, described herein, addressesthese challenges and describes protocols that reduce the formation ofCompound II-OH significantly.

In some embodiments, Compound I is synthesized by a reaction betweenCompound II and Compound III. In some embodiments, Compound II-OH isreacted with a chlorinating reagent to form Compound II-Cl. In someembodiments, Compound II-Cl reacts with Compound III to produce CompoundI.

In some embodiments, Compound II-OH is dissolved in a solvent and achlorinating reagent is added to yield Compound II-Cl. In someembodiments, the solvent used include, but are not limited to,tetrahydrofuran (THF), dimethylforamide (DMF), diethylether, andmethylene chloride (DCM). In one embodiment, the solvent is methylenechloride.

Previous process utilized THF as the solvent for the acid chlorideformation with the addition of DMF. It was discovered that the formationof Compound II-OH could be minimized when DCM is used as the solvent forthe acid chloride formation.

Prior to the addition of the chlorinating reagent, the solutioncontaining Compound II-OH is cooled below ambient temperature. In someembodiments, the solution containing Compound II-OH is cooled to about10° C. to about 15° C. In some embodiments, the chlorinating reagent isadded over about 10 minutes to about 30 minutes while the temperature ofthe solution was maintained below ambient temperature. In someembodiments, the mixture is maintained at about 10° C. to about 15° C.and stirred for about 2 hours to about 4 hours then cooled to about 0°C. or below. In one embodiment, the reaction was stirred until HPLCanalysis indicated ≤3.0% of Compound II-OH is present.

Non-limiting examples of chlorinating reagents include thionyl chloride,phosphorous trichloride, phosphorus pentachloride, phosphorusoxychloride, oxalyl chloride, phosgene, and the like or the combinationsthereof. In one embodiment, the chlorinating reagent is thionylchloride. In another embodiment, the chlorinating reagent is used inabout 1.0 equiv to about 2.0 equiv with respect to Compound II-OH. Inone embodiment, the chlorinating reagent is used in about 1.0 equivalentto about 1.1 equiv with respect to Compound II-OH. In anotherembodiment, the ratio of the chlorinating reagent and the Compound II-OHis about 1:1.

In a separate reaction vessel, Compound III is dissolved in a solventwith a base. To the solution of Compound III and a base, a solution ofCompound II-Cl is slowly added. In some embodiment, the solvent used fordissolving Compound III can be tetrahydrofuran, dimethylforamide,diethylether, methylene chloride, and mixtures thereof. In oneembodiment, the solvent is methylene chloride. In some embodiments, thereaction is cooled to about 0° C. before the addition of Compound III.In one embodiment, the reaction is maintained at about 0° C. for about 3hours to about 7 hours after the addition of Compound III until HPLCanalysis indicates ≤0.5% of Compound II-Cl is present. In anotherembodiment, Compound III is used in about 1.0 equiv to about 1.2 equivwith respect to Compound II-OH.

In some embodiments, the base is used in about 1 equiv to about 4 equiv.Non-limiting example of base includes alkali carbonates (potassiumcarbonate, sodium carbonate, cesium carbonate, etc), alkali metalhydrogen carbonates (potassium bicarbonate, sodium bicarbonate, etc),alkaline metal acetates (potassium acetate, sodium acetate, etc),alkaline metal phosphates (potassium phosphate, sodium phosphate, etc),alkali metal fluorides (potassium fluoride, cesium fluoride, etc),alkaline metal alkoxides (potassium tert-butoxide, sodium tert-butoxide,etc), alkali metal hydroxides (potassium hydroxide, sodium hydroxide,etc), and organic bases such as alkyl amines (triethylamine,diisopropylamine, diisopropylethyl amine, etc) pyridines (pyridine,dimethylaminopyridine, etc), cyclic amines (morpholine,4-methylmorpholine, etc), and the combinations thereof. In oneembodiment, the base is pyridine. In some embodiments, pyridine reactswith Compound II-Cl to form pyridine-HCl salt and vigorous agitation maybe necessary to prevent aggregation of the salt.

Upon the indication of the conversion of Compound II-Cl to Compound I,the reaction mixture is, in one embodiment, acidified. In someembodiments, citric acid solution is used to acidify the reactionmixture containing crude Compound I. In one embodiment, citric acid isused in about 1.5 equiv to about 2.0 equiv in about 10 parts water withrespect to Compound II-OH and added over about 30 minutes to about 1hour. In one embodiment, a chilled citric acid aqueous solution is addedto a cooled reaction mixture while maintaining an internal temperatureof about 0° C.

In some embodiments, the volatile solvent is removed to provide a totalvolume of about 13 parts. In other embodiments, a different solvent isadded (about 5 parts) to the reduced reaction mixture, and reduced onceagain to provide a total volume of about 13 parts. In some embodiments,a polar solvent such as ethyl acetate is used. In other embodiment, thesolvent is removed under reduced pressure.

The reduced reaction mixture which consists of a majority of an acidicaqueous layer, in some embodiments, is extracted with a polar solventsuch as ethyl acetate in about 10 parts. In some embodiments, theorganic layer containing the desired product, Compound I, is washed withaqueous solutions several times, for example with a solution of sodiumbicarbonate and brine.

The stability of Compound I during workup procedure was studied. It wasdemonstrated that Compound I is not particularly sensitive to lightduring workup and the use of clear reaction vessel or an amber reactionvessel did not display increased hydrolysis of Compound I to CompoundII-OH. Additionally, Compound I was studied in various pH andtemperature during workup procedures; however, no correlation wasdiscovered for increased hydrolysis of Compound I to Compound II-OH.Although it is still a possibility that Compound I can hydrolyze toCompound II-OH during workup, the amide bond is fairly stable under theworkup conditions.

Water content in the organic layer resulting from the extraction workupis found to have an impact on the overall yield of the salt formation ofCompound I (Compound I-MsOH). In some embodiments, the presence of waterduring the salt formation increased the hydrolysis of Compound I back toCompound II-OH, thus a rigorous drying process is ideal. In someembodiments, the organic layer, containing Compound I, is dried with 3 Åpowdered molecular sieves. In some embodiments, the resulting slurry isstirred for about 15 hours to about 30 hours at an ambient temperaturebefore the molecular sieves are removed by filtration. The filteredmolecular sieves are washed with a polar solvent such as ethyl acetate.In some embodiments, the residual water content is determined bytitration. In some embodiments, the drying step using molecular sievescan be repeated until the residual water is ≤2.5%.

Once the organic layer containing Compound I is dried and determined tobe substantially free of water, in some embodiments, the solvent isremoved to give a total volume of about 3 parts. In some embodiments,the solvent is removed by distillation. In other embodiment, thesolution is assayed by HPLC before or after the solvent reduction tocalculate the amount of Compound I present.

Alternatively, in one embodiment, Compound I is synthesized fromCompound II and Compound III using coupling reaction conditions commonlyknown in the art, using reagents including but are not limited tocarbodiimides, 1-hydroxybenzotriazole,hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide,1-hydroxy-7-aza-1H-benzotriazole,2-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetrafluoroborate/hexafluorophosphate,2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate, and/or2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate, 2-propanephosphonic acid anhydride, and1,1′-carbonyldiimidazole.

Preparation of Compound I-MsOH

To the concentrated crude solution of Compound I, in some embodiments, asolvent is added in about 4 parts. In one embodiment, the solvent usedis acetonitrile. To the solution containing Compound I, methane sulfonicacid (MsOH) is added. In some embodiments, MsOH is added in a singleportion. In other embodiments, MsOH is used in about 0.9 equiv to about1.5 equiv with respect to Compound I as determined by the HPLC assay. Inone embodiment, MsOH is used in about 0.97 equiv to about 1.02 equiv.

In some embodiments, MsOH is washed into solution containing Compound Iand MsOH with additional solvent such as acetonitrile or ethyl acetate.The reaction mixture is stirred at an ambient temperature for about 30minutes to about 1 hour. It was discovered that excess MsOH had anadverse effect on the formation of Compound II-OH by hydrolysis of theamide bond of Compound I, therefore an accurate assay of Compound I iscritical to determine the exact amount of Compound I present and theexact amount of MsOH required to achieve a 1:1 stoichiometric ratioduring salt formation. In one embodiment, Compound I and MsOH are usedin 1:1 ratio to minimize amide bond hydrolysis.

In one embodiment, the solvent used in the step of converting Compound Iinto Compound I-MsOH, is free of alcohol solvents. It was discoveredthat residual levels of alcohol solvents (e.g., methanol, ethanol, etc.)in the reaction lead to contamination of Compound I-MsOH with mesylateesters. These resulting mesylate esters are known mutagens.

In some embodiments, prior to crystallization, the reaction mixture waswashed with brine and dried using 3 Å molecular sieves. In some cases,it was determined that slight amount of water present in the reactionmixture could prevent crystallization to occur and/or result in loweryield of Compound I-MsOH. Not wishing to be bound by any theory, thelower yield resulted in systems with higher water content is due tohigher hydrolysis rate to give Compound II-OH which was found in themother liquor at a higher concentration in a study with higher watercontent.

To crystalize Compound I-MsOH from the reaction mixture, in someembodiments, a pure sample of Compound I-MsOH is used as a seed. Thesolution, with or without seeding, is in some embodiments, stirred at anambient temperature for about 6 hours to about 10 hours. Additionally,in some embodiments, the solution is stirred at about 0° C. for about 6hours to about 10 hours. The precipitated crystals are, in someembodiments, collected by filtration. In some embodiments, the crystalsare washed with cold solvent such as ethyl acetate to obtain crudeCompound I-MsOH.

The crude crystals of Compound I-MsOH are, in some embodiments, furtherpurified using hot recrystallization technique. In some embodiments,crystals of Compound I-MsOH are dissolved in solvents (about 10 parts)at an elevated temperature. In other embodiments, crystals of CompoundI-MsOH are dissolved in acetonitrile at about 70° C. The hot solution ofCompound I-MsOH was slowly cooled to about 50° C. to about 55° C. over aperiod of about 1 hour. In some embodiments, the solution of CompoundI-MsOH was seeded with pure sample of Compound I-MsOH at about 50° C. toabout 55° C. The solution, with or without seeding, is stirred at about50° C. to about 55° C. for about 4 hours to about 8 hours, in someembodiments. The hot solution is, in some embodiments, cooled to anambient temperature over about 1 hour and stirred at an ambienttemperature for about 6 hours to about 10 hours. In one embodiment, hotrecrystallization of Compound I-MsOH from acetonitrile reducescontamination, including mesylate esters.

The precipitated crystals of Compound I-MsOH, in some embodiments, arecollected by filtration. In other embodiments, the filtered crystals ofCompound I-MsOH are washed with acetonitrile. In one embodiment, thefiltered crystals of Compound I-MsOH are washed with cold acetonitrile.The purity of the crystals is assayed by titration and HPLC. Ifnecessary, hot recrystallization can be repeated until the desiredpurity is obtained. In some embodiments, the filtered crystals ofCompound I-MsOH are dried under reduced pressure. In other embodiments,the dried crystals are further pulverized by a powder mill and a jetmill or the like.

The study of the Compound I-MsOH crystals under a microscope revealedthat the surface of the crystals became oily with time, which isidentified as a result of hydrolysis on the surface of the crystals.Acetonitrile was found to be a solvent that Compound II-OH is moresoluble in than Compound I-MsOH. Therefore, upon recrystallization, itis beneficial to wash the filtered crystals with acetonitrile. Due toCompound I-MsOH also being soluble in acetonitrile to some degree, insome embodiments, cold acetonitrile should be used to wash the crystals,and the volume and the frequency of the wash should be limited to abouttwice with about 2 parts volume to about 3 parts volume.

The hydrolysis of Compound I or Compound I-MsOH is susceptible in thepresence of water or acid. In some embodiments, the reaction mixtureshould be substantially free of water prior and during purificationsteps of Compound I-MsOH. In other embodiments, the reaction mixtureshould be substantially free of aqueous acid prior and duringpurification steps of Compound I-MsOH. In some embodiments, gentleagitation should be maintained through the salt formation andpurification steps of Compound I-MsOH.

In some embodiments, Compound III used in the reaction to obtainCompound I or Compound I-MsOH is optically pure. In which case, it willresult in an optically pure Compound I or optically pure CompoundI-MsOH. In one embodiment, Compound III is (S)-Compound III. In anotherembodiment, Compound I-MsOH is (S)-Compound I-MsOH.

The disclosed process of the synthesis of Compound II-OH and itssubsequent use in the disclosed process of the synthesis of CompoundI-MsOH, in some embodiments, results in highly pure Compound I-MsOH thatis substantially free of Compounds I-MsOH-A, I-MsOH-B, I-MsOH-C,I-MsOH-D, I-MsOH-E, I-MsOH-F, I-MsOH-G, II-OH, III, VI, VII, VIII, IX,and mesylate esters resulting from MsOH. In some embodiments, CompoundI-MsOH, e.g., synthesized by the disclosed process, disclosed hereinwill result in >96% purity. In other embodiments, Compound I-MsOH, e.g.,synthesized by the disclosed process, disclosed herein will resultin >97% purity. In one embodiment, Compound I-MsOH, e.g., synthesized bythe disclosed process, disclosed herein will result in >98% purity. Inanother embodiment, Compound I-MsOH, e.g., synthesized by the disclosedprocess, disclosed herein will result in >99% purity.

The disclosed process of the synthesis of Compound II-OH and itssubsequent use in the disclosed process of the synthesis of CompoundI-MsOH, in some embodiments, results in highly pure (S)-Compound I-MsOHthat is substantially free of (R)-Compound I-MsOH, R or S versions of(I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-D, I-MsOH-E, I-MsOH-F, I-MsOH-G),II-OH, III, VI, VII, VIII, IX, and mesylate esters resulting from MsOH.In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, disclosed herein will result in >96% purity. In otherembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, disclosed herein will result in >97% purity. In one embodiment,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,disclosed herein will result in >98% purity. In another embodiment,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process,disclosed herein will result in >99% purity.

In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤0.2% of each impurities includingCompounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F, I-MsOH-G, VII, VIII,and IX. In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤1.0%, ≤0.8%, ≤0.6%, or ≤0.4% of eachimpurities including I-MsOH-D and Compound II-OH. In other embodiments,Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤1,500 ppm of Compound III. In another embodiment, CompoundI-MsOH, e.g., synthesized by the disclosed process, will contain ≤0.3%of each impurities including Compounds I-MsOH-C, I-MsOH-E, and I-MsOH-F.In some embodiments, Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤0.002% (20 ppm) mesylate ester resulting fromMsOH. In some embodiments, Compound I-MsOH contains ≤0.002% (20 ppm)mesylate ester for a 150 mg dose. In some embodiments, Compound I-MsOHcontains ≤15 ppm mesylate ester for a 150 mg dose. In one embodiment,Compound I-MsOH contains ≤0.001% (10 ppm) mesylate ester for a 150 mgdose.

In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤0.3% of each impurities includingCompounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F, I-MsOH-G, VII, VIII,and IX. In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤0.5% of each impurities includingI-MsOH-D and Compound II-OH. In other embodiments, Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤1,000 ppm ofCompound III. In another embodiment, Compound I-MsOH, e.g., synthesizedby the disclosed process, will contain ≤0.15% of each impuritiesincluding Compounds I-MsOH-C, I-MsOH-E, and I-MsOH-F, VII, VIII, and IX.In some embodiments, Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤0.001% (10 ppm) mesylate ester resulting fromMsOH.

In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤0.05% of each impurities includingCompounds I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F, I-MsOH-G, VII, VIII,and IX. In other embodiments, Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤0.30% of each impurities includingCompound I-MsOH-D and Compound II-OH. In some embodiments, CompoundI-MsOH, e.g., synthesized by the disclosed process, will contain ≤0.1%of each impurities including I-MsOH-A, I-MsOH-B, I-MsOH-C, I-MsOH-F,I-MsOH-G, VII, VIII, and IX. In other embodiments, Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤0.15% of eachimpurities including Compound I-MsOH-D and Compound II-OH. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤1.0% of (R)-Compound I-MsOH. In anotherembodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤0.5% of (R)-Compound I-MsOH. In one embodiment,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤0.25% of (R)-Compound I-MsOH. In one embodiment, (S)-CompoundI-MsOH, e.g., synthesized by the disclosed process, will contain ≤0.20%of (R)-Compound I-MsOH.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤5.0% w/w water content as measured byU.S. Pharmacopeia (USP) <921>, method 1C. In some embodiments,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤2.5% w/w water content as measured by USP <921>, method 1C. Insome embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤2.0% w/w water content as measured byUSP <921>, method 1C. In some embodiments, (S)-Compound I-MsOH, e.g.,synthesized by the disclosed process, will contain ≤1.0% w/w watercontent as measured by USP <921>, method IC.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤20% w/w methanesulfonic acid. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤15% w/w methanesulfonic acid. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤13% w/w methanesulfonic acid. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain between about 5% to about 15% w/w methanesulfonicacid. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain between about 11% to about 13% w/wmethanesulfonic acid.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤500 ppm acetonitrile as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤425 ppm acetonitrile as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤410 ppm acetonitrile as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤350 ppm acetonitrile as residualsolvent.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤7500 ppm ethyl acetate as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤5000 ppm ethyl acetate as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤4000 ppm ethyl acetate as residualsolvent.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤300 ppm pyridine as residual solvent.In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤200 ppm pyridine as residual solvent.In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤100 ppm pyridine as residual solvent.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤750 ppm dichloromethane as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤600 ppm dichloromethane as residualsolvent. In some embodiments, (S)-Compound I-MsOH, e.g., synthesized bythe disclosed process, will contain ≤500 ppm dichloromethane as residualsolvent.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤1.0 ppm elemental impurities of cadmiumas measured by USP <232> and/or ≤1.0 ppm lead. In some embodiments,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤0.5 ppm elemental impurities of cadmium as measured by USP<232> and/or ≤0.5 ppm lead. In some embodiments, (S)-Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤0.25 ppmelemental impurities of cadmium as measured by USP <232> and/or ≤0.25ppm lead.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤2.0 ppm elemental impurities of arsenicas measured by USP <232>. In some embodiments, (S)-Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤1.5 ppmelemental impurities of arsenic as measured by USP <232>. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤1.0 ppm elemental impurities of arsenic asmeasured by USP <232>.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤10.0 ppm elemental impurities ofmercury as measured by USP <232> and/or ≤10.0 ppm cobalt. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤5.0 ppm elemental impurities of mercury asmeasured by USP <232> and/or ≤5.0 ppm cobalt. In some embodiments,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤3.0 ppm elemental impurities of mercury as measured by USP<232> and/or ≤2.5 ppm cobalt. In one embodiment, (S)-Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤2.0 ppmelemental impurities of mercury as measured by USP <232>. In oneembodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤2.0 ppm elemental impurities of cobalt asmeasured by USP <232>.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤20.0 ppm elemental impurities ofvanadium as measured by USP <232> and/or ≤20.0 ppm palladium. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤10.0 ppm elemental impurities of vanadium asmeasured by USP <232> and/or ≤10.0 ppm palladium. In some embodiments,(S)-Compound I-MsOH, e.g., synthesized by the disclosed process, willcontain ≤5.0 ppm elemental impurities of vanadium as measured by USP<232> and/or ≤5.0 ppm palladium.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤30.0 ppm elemental impurities of nickelas measured by USP <232>. In some embodiments, (S)-Compound I-MsOH,e.g., synthesized by the disclosed process, will contain ≤20.0 ppmelemental impurities of nickel as measured by USP <232>. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤10.0 ppm elemental impurities of nickel asmeasured by USP <232≥.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤1500 ppm elemental impurities ofchromium as measured by USP <232≥. In some embodiments, (S)-CompoundI-MsOH, e.g., synthesized by the disclosed process, will contain ≤1250ppm elemental impurities of chromium as measured by USP <232>. In someembodiments, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤1100 ppm elemental impurities of chromium asmeasured by USP <232>. In one embodiment, (S)-Compound I-MsOH, e.g.,synthesized by the disclosed process, will contain ≤1000 ppm elementalimpurities of chromium as measured by USP <232>.

In some embodiments, (S)-Compound I-MsOH, e.g., synthesized by thedisclosed process, will contain ≤500 ppm elemental impurities ofmolybdenum as measured by USP <232>. In some embodiments, (S)-CompoundI-MsOH, e.g., synthesized by the disclosed process, will contain ≤300ppm elemental impurities of molybdenum as measured by USP <232>. In oneembodiment, (S)-Compound I-MsOH, e.g., synthesized by the disclosedprocess, will contain ≤250 ppm elemental impurities of molybdenum asmeasured by USP <232≥.

EXAMPLES

Unless otherwise noted, the purity of the compounds was assessed usingstandard HPLC analysis. For example, a CAPCELL PAK® C18 column (Shisedo)with the dimensions of 4.6 cm×150 cm, 5 micron was used with a PDA 290nm detector. The column temperature was set to 40° C., and the twomobile phases were A: 100% 0.05M NH₄OAc in water and B: 100%acetonitrile. The flow rate was set at 1.0 mL/min with the run time ofabout 45-60 minutes per sample. The injection volume was 10 μL. In adifferent system, Clark instrument was used with PDA 293 nm detector.The injection volume was 20 μL and the run time was 120 minutes persample.

Example 1: Optimization of Suzuki Coupling with Pd(PPh₃)₄ System

Table 1 describes the optimization efforts for the Suzuki couplingreaction using Pd(PPh₃)₄ catalyst system between Compound IV andCompound V-OMe. The reaction represented in Table 1 used Compound IV (5g, 1 equiv), Compound V-OMe (2 equiv), and base (6.3 equiv) in solvent(ratio v/w with respect to Compound IV) and heated at reflux. Thisseries of experiments show varying the reaction conditions did result insome reduction of impurity Compound VIII using the Pd(PPh₃)₄ system,although stalling or failure to recrystallize product was observed undermost conditions.

TABLE 1 Base Exp. Solvents # Catalyst (ratio) Comments 1 Pd(OAc)₂/PPh₃K₃PO₄ 3 h: 50% conversion 2.0/8.0 mol % THF:water 6 h: 75% conversion(25:8) Compound VIII: 0.25% 2 Pd(PPh₃)₄ K₃PO₄ 4 h: 65% conversion 2.0mol % THF:water Compound VIII: 0.135% (25:8) 3 Pd(OAc)₂/PPh₃ K₃PO₄Grignard refluxed 27 h 2.0/8.0 mol % THF:water 4 h: 64% conversion(25:8) Compound VIII: 0.22% 4 Pd(OAc)₂/PPh₃ K₃PO₄ Using 1 equiv. boronicester 2.0/8.0 mol % THF:water 8 h: 50% conversion (25:8) Compound VIII:0.11% 5 Pd(OAc)₂/PPh₃ K₃PO₄ At 45° C. instead of refluxing 2.0/8.0 mol %THF:water 27 h: 100% conversion (25:8) Compound VIII: 0.15% 6Pd(OAc)₂/PPh₃ K₃PO₄ 4 h: 100% conversion 10.0/40.0 mol % THF:waterCompound VIII: 0.04% (25:8) Trituration failed to produce crystals

Example 2: Optimization of Suzuki Coupling with Pd Catalyst System

Table 2 outlines the optimization efforts for the Suzuki couplingreaction using Pd(PPh₃)₄ catalyst system between Compound IV andCompound V-OMe. The reaction represented in Table 2 used Compound IV (5g, 1 equiv), Compound V-OMe (2 equiv), and base (6.3 equiv) in solvent(ratio v/w with respect to Compound IV) and heated at reflux. Accordingto the results from Table 2, the Pd(OAc)₂/P(o-tol)₃ system usessignificantly less catalyst, significantly less phosphine ligand andgenerally always proceeded to completion within 2 hours with no stallingobserved, even without degassing. The Pd(OAc)₂/P(o-tol)₃ catalyst systemproduced Compound II-OH in increased yield and increased purity (>99%)when compared to the original Pd(PPh₃)₄ catalyst system. Additionally,this series of experiments also show varying the reaction conditions didnot result in significant reduction of impurity Compound VIII comparedwith the Pd(PPh₃)₄ systems.

TABLE 2 Base Exp. Solvents # Catalyst (ratio) Comments 1 Pd(OAc)₂ K₂CO₃27 h: 17% conversion 10.0 mol % THF:water Compound VIII: 0.15% (25:8) 2Pd(dba)₂/PtBu₃ K₃PO₄ 4 h: 100% conversion 2.0/8.0 mol % THF:waterCompound VIII: 0.15% (25:8) Trituration failed to produce crystals 3Pd(OAc)₂/P(o-tol)₃ K₂CO₃ 2 h: 100% conversion 2.0/8.0 mol % THF:waterCompound VIII: 0.08% (25:8) Compound II-OH² > 99% purity 4Pd(OAc)₂/P(o-tol)₃ K₂CO₃ 1 h: 100% conversion 2.0/8.0 mol % THF:waterCompound VIII: 0.06% (25:8) Compound II-OH² > 99% purity 5Pd(OAc)₂/P(o-tol)₃ K₂CO₃ 100% conversion 1.0/2.0 mol % THF:waterCompound VIII: 0.15% (25:8) Compound II-OH² > 99% purity. 6Pd(OAc)₂/P(o-tol)₃ K₂CO₃ 1.5 h. 100% conversion 0.5/1.0 mol % THF:waterCompound VIII: 0.13% (25:8) Compound II-OH² > 99% purity 7Pd(OAc)₂/P(o-tol)₃ K₂CO₃ 2 h: 100% conversion 0.25/0.5 mol % THF:waterCompound VIII: 0.17%, 0.38%¹ (25:8) Compound II-OH² > 99% purity 8Pd(OAc)₂/P(o-tol)₃ K₂CO₃ Reaction was degassed for 4 h 0.25/0.5 mol %THF:water 2 h: 100% conversion (25:8) Compound VIII: 0.28% CompoundII-OH² > 99% purity 9 Pd(OAc)₂/P(o-tol)₃ K₂CO₃ Reaction was not degassed0.25/0.5 mol % THF:water 2 h: 100% conversion (25:8) Compound VIII:0.29% Compound II-OH² > 99% purity ¹Showing results of two differenttrials. ²Compound II-OH was triturated.

Example 3: Synthesis of Compound II-OH, with Recrystallization

Anhydrous tetrahydrofuran (THF, 9 parts) was added to magnesium (0.185kg, 2.15 equiv) and the solution was stirred for 1 hour. THF was removedby distillation until the total volume of the solution was about 3parts. To that, neat Compound VI (0.775 kg, 0.4 equiv) was added and thesolution was heated to about 66° C. for 2 hours. The reaction was cooledto about 55° C. and additional anhydrous THF (5 parts) was added. To thehot solution, neat Compound VI (1.163 kg, 1.6 equiv) was added over 1hour and the mixture was stirred at about 55° C. for about 4 hours toform the Grignard reagent. After HPLC analysis indicated less than about1% of Compound VI was remaining, the reaction mixture was cooled toabout −25° C. To the cooled reaction mixture, neat trimethoxyborane(0.739 kg, 2.0 equiv) was added portion-wise over 2 hours. The resultingmixture was stirred at −25° C. for 1 hour then warmed up to about 20° C.and stirred for 1 hour to yield Compound V-OMe.

To the reaction mixture containing Compound V-OMe, a solution ofpotassium carbonate (3.06 kg, 6.25 equiv) in water (5.5 parts) wasportion-wise added over 1 hour. The biphasic solution was degassed withnitrogen for 1 hour then palladium acetate (0.002 kg, 0.0025 equiv) andtri-o-tolylphosphine (0.0054 kg, 0.0050 equiv) was added, whiledegassing continued. Subsequently, Compound IV (1.200 kg, 1.0 equiv) wasadded while degassing continued. The resulting reaction mixture wasstirred at or below 65° C. for 4 hours or until HPLC analysis indicated≤2% Compound IV was remaining. Once the reaction was deemed complete, itwas cooled to an ambient temperature.

The reaction mixture was acidified using aqueous hydrochloric acid untilthe pH was adjusted to about 2.0-3.0. Once acidified, the layers wereseparated and the aqueous layer was extracted with toluene (10 parts).The combined organic layers were distilled to an approximate volume of6.5 parts then Celite® (0.6 w/w, 0.720 kg) and Draco KBG (0.3 w/w, 0.360kg, charcoal) were added and stirred for 3 hours at about 20° C. Thecharcoal and Celite® were removed by filtration and the filtrate wasconcentrated under reduced pressure to afford a volume of about 3 parts.

To the reduced solution, isopropanol (5 parts) was added and the mixturewas again concentrated to a volume of 3 parts. To the resulting oil,heptanes (12 parts) were added portion-wise over 1 hour. The resultingsuspension was stirred at about 20° C. for 6 hours and the crystals werecollected by filtration.

The crude crystals collected by the filtration were then dissolved inethyl acetate (0.4 parts) and isopropanol (3.6 parts) at 70° C. Thetemperature of the solution was reduced by 10° C. every 1 hour until thetemperature reached 20° C. The solution was stirred at 20° C. for 4hours and the crystals were collected by filtration and washed withheptanes. Compound II-OH was dried to yield 0.938 kg of yellow solid(58.5% yield, 99.42% purity).

HPLC purity method:

-   -   Column: CAPCELL PAK® C18, Shisedo, 4.6×150 cm, 5 micron    -   Detector wavelength: PDA 290 nm    -   Column temperature: 40° C.    -   Mobile phase: A: 100% 0.05M NH₄OAc in water        -   B: 100% ACN    -   Flow rate: 1.0 mL/min    -   Run time: 45 minutes.    -   Injection volume: 10 μL

Gradient Table:

Time (min) % A % B 0 90 10 5 90 10 8 10 90 10 10 90 11.01 90 10 20 90 10Compound VI=8.3 minuteCompound V=2.3-2.6 minutes (three species in the mixture: CompoundV-(OMe)2,Compound V-(OMe)(Ar₁), and Compound V-(Ar₁)(Ar₂))Compound IV=3.0 minuteCompound II-OH=8.3 minute; purity=99.42%.

Example 4: Synthesis of Compound II-OH, with In Situ Generated CompoundV Versus Crystalline, Isolated Compound V-OH

To the reaction mixture containing either a) 2.0 equiv of in situsolution of Compound V-OMe or b) 2.0 equiv solution of Compound V-OH inwater/THF prepared by dissolving isolated and crystalline Compound V-OHin water/THF, a solution of potassium carbonate (3.03 g, 6.25 equiv) inwater (5.5 parts) was portion-wise added over 1 hour. The biphasicsolution was degassed with nitrogen for 1 hour then palladium acetate(0.002 g, 0.0025 equiv) and tri-o-tolylphosphine (0.0045 g, 0.0050equiv) was added, while degassing continued. Subsequently, Compound IV(1.00 g, 1.0 equiv) was added while degassing continued. The resultingreaction mixture was stirred at or below 65° C. for 4 hours or untilHPLC analysis indicated ≤2% Compound IV was remaining. Once the reactionwas deemed complete, it was cooled to an ambient temperature.

The reaction mixture was acidified using aqueous hydrochloric acid untilthe pH was adjusted to about 2.0-3.0. Once acidified, the layers wereseparated and the aqueous layer was extracted with toluene (10 parts).The combined organic layers were distilled to an approximate volume of6.5 parts then Celite® (0.6 w/w, 0.600 kg) and Draco KBG (0.3 w/w, 0.300g, charcoal) were added and stirred for 3 hours at about 20° C. Thecharcoal and Celite® were removed by filtration and the filtrate wasconcentrated under reduced pressure to afford a volume of about 3 parts.

To the reduced solution, isopropanol (5 parts) was added and the mixturewas again concentrated to a volume of 3 parts. To the resulting oil,heptanes (12 parts) were added portion-wise over 1 hour. The resultingsuspension was stirred at about 20° C. for 6 hours and the crystals werecollected by filtration. Compound II-OH was dried to yield a yellowsolid (Table 3 shows yield, purity and related substances). The HPLCcondition from Example 3 was used to assess the purity represented inTable 3.

TABLE 3 In situ Generated Crystalline, Isolated Compound Compound V—OMeV—OH Condition Yield (%) 70 67 of Compound II-OH Product Analysis byHPLC Compound IV-OH (% area) 0.01 0.00 Compound II-OH-A (% area) 0.070.00 Compound II-OH-B (% area) 0.05 0.00 Compound II-OH (% area) 99.2199.71 Compound II-OH-C (% area) 0.16 0.06 Compound VIII (% area) 0.100.00

Table 3 indicates that using crystalline, isolated compound V-OH inreaction with Compound IV reduced the impurities, namely Compound IV-OH,Compound II-OH-A, Compound II-OH-B, Compound II-OH-C, and Compound VIII.In particular, the presence of Compound IV-OH, Compound II-OH, CompoundOH-B, and Compound VIII were reduced below detection. Further, thepresence of Compound II-OH-C was also significantly reduced from 0.16%to 0.06%.

Previous synthesis utilized in situ solution of Compound V-OMe inreaction with Compound IV to prepare Compound II-OH. This reactionproduced impurities of Compound IV-OH, Compound II-OH-A, CompoundII-OH-B, Compound II-OH-C, and/or Compound VIII, which were verydifficult to eliminate and necessitating multiple recrystallizationpurifications in order to provide Compound II-OH that met the impurityspecifications. See, e.g., WO 2016/105527, the contents of thispublication are herein incorporated by reference in their entirety forall intended purposes.

Thus, by substituting in situ solution of Compound V-OMe with a solutionprepared from a crystalline and isolated Compound V-OH significantlyreduced the purification process for Compound V-OH. In some embodiment,only one purification step is required when using crystalline andisolated Compound V-OH in reaction with Compound IV. In one embodiment,the purity of Compound II-OH is higher when prepared from crystallineand isolated Compound V-OH in reaction with Compound IV when comparedfrom the purity of Compound II-OH prepared from in situ solution ofCompound V-OMe in reaction with Compound IV.

In one embodiment, Compound II-OH prepared from crystalline, isolatedCompound V-OH has about ≤0.01% of Compound II-OH-A, about ≤0.01% ofCompound II-OH-B, and/or about ≤0.10% of Compound II-OH-C. In anotherembodiment, Compound II-OH prepared from crystalline, isolated CompoundV-OH has about ≤0.01% of Compound II-OH-A, about ≤0.01% of CompoundII-OH-B, and about ≤0.10% of Compound II-OH-C.

Example 5: Compound V-OH and Compound V-3

Compound V-3 was formed during prolonged drying of Compound V-OH athigher temperatures, resulting in loss of water. Compound V-3 formationwas observed when Compound V-OH was subject to drying to achieve loss ondrying (LOD) below about 0.5%. As shown in FIG. 2, Compound V-3 (topspectrum) is characterized by a ¹H NMR doublet in the 8.1-8.2 ppm regionwhereas Compound V-OH (bottom spectrum) is characterized by ¹H NMRdoublet in the 7.8-7.6 ppm region. FIG. 3 shows the aromatic region ofthe ¹H NMR spectra of FIG. 2. The conversion of Compound V-3 to CompoundV-OH in the presence of water was observed when D₂O is added to the ¹HNMR sample of Compound V-3 (FIG. 2, middle spectrum).

As demonstrated above, Compound V-3 readily converts to Compound V-OHunder aqueous conditions, thus, in one embodiment, Compound V-3 andCompound V-OH can be used interchangeably or as a mixture in thereaction with Compound IV to prepare Compound II-OH. In one embodiment,when Compound V-3 is used in the reaction with Compound IV, about onethird molar equivalence (compared to Compound V-OH) is necessary.

Example 6: Synthesis of Compound I-MsOH

Compound II-OH (34.7 kg, 1.0 equiv) was dissolved in dichloromethane (5parts) and cooled to about 10-15° C. Neat thionyl chloride (10.1 kg,1.10 equiv) was added portion-wise over 10 minutes and the mixture wasstirred at about 10-15° C. for 3 hours. After HPLC analysis indicated≤3% Compound II-OH was remaining, the reaction mixture was cooled to 0°C. A solution of (S)-Compound III (21.2 kg, 1.05 equiv) and pyridine(21.3 kg, 3.5 equiv) in dichloromethane (6 parts) was separatelyprepared and cooled to 0° C. To the solution of (S)-Compound III, theacid chloride solution was slowly added at 0° C. and stirred for 5hours.

Upon completion of the reaction as indicated by HPLC analysis showingCompound II-Cl is ≤0.5%, a chilled solution of citric acid (27.7 kg, 1.7equiv) in water (10 parts) was added over 30 minutes while maintainingan internal temperature of 0° C. Dichloromethane was removed underreduced pressure to a total volume of about 13 parts then ethyl acetate(5 parts) was added and the volume was again reduced under pressure toabout 13 parts. The resulting residue was extracted with ethyl acetate(10 parts) and the organic layer was washed with aqueous solution ofsodium bicarbonate (41.7 kg, 6.45 equiv) in water (10 parts) and thewash was repeated. The organic layer is further washed with brine (10parts).

To the resulting organic layer was added 3 Å powdered molecular sieves(100% w/w, 34.8 kg) and the slurry was stirred for 20 hours thenfiltered. The filter cake was washed with ethyl acetate (2 parts). Thedried organic layer containing Compound I was assayed by HPLC todetermine the amount present. To the solution, acetonitrile (4 parts)was added then methanesulfonic acid (6.9 kg, 1.01 equiv) was added inone portion. Ethyl acetate (1 part) was used to transfer all of themethane sulfonic acid. The mixture was stirred at 20° C. for about 30minutes.

The reaction mixture was then seeded with (S)-Compound I-MsOH and themixture was stirred at 20° C. for 8 hours. The precipitated crystalswere collected by filtration and washed with chilled ethyl acetate (1part). The crude crystals were dissolved in acetonitrile (10 parts) at70° C. and the solution was cooled to 50-55° C. over 1 hour and seededwith (S)-Compound I-MsOH. The solution was stirred at 50-55° C. for 6hours then cooled to 20° C. over 1 hour then stirred for 8 hours. Theprecipitated crystals were collected by filtration and washed twice withchilled acetonitrile (2.5 parts each). The crystals were dried toprovide 47.72 kg of (S)-Compound I-MsOH as a bright yellow solid (78%yield, 99.10% purity). The dried crystals were then pulverized by apowder mill and jet mill to give the final product composition.

HPLC purity method:

-   -   Column: CAPCELL PAK® C18, Shisedo, 4.6×150 cm, 5 micron    -   Detector wavelength: PDA290 nm    -   Column temperature: 40° C.    -   Mobile phase: A: 100% 0.05M NH₄OAc in water        -   B: 100% ACN    -   Flow rate: 1.0 mL/min    -   Run time: 60 minutes    -   Injection volume: 10 μL

Gradient Table:

Time (min) % A % B 0 55 45 20 55 45 25 95 5 48 95 5 50 55 45 60 55 45 6155 45 62 55 45

Compound II-OH=18.54 min Compound I/Compound I-MsOH=26.05

It should be understood that the above description is onlyrepresentative of illustrative embodiments and examples. For theconvenience of the reader, the above description has focused on alimited number of representative examples of all possible embodiments,examples that teach the principles of the disclosure. The descriptionhas not attempted to exhaustively enumerate all possible variations oreven combinations of those variations described. That alternateembodiments may not have been presented for a specific portion of thedisclosure, or that further undescribed alternate embodiments may beavailable for a portion, is not to be considered a disclaimer of thosealternate embodiments. One of ordinary skill will appreciate that manyof those undescribed embodiments, involve differences in technology andmaterials rather than differences in the application of the principlesof the disclosure. Accordingly, the disclosure is not intended to belimited to less than the scope set forth in the following claims.

INCORPORATION BY REFERENCE

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes. However, mention of any reference,article, publication, patent, patent publication, and patent applicationcited herein is not, and should not be taken as acknowledgment or anyform of suggestion that they constitute valid prior art or form part ofthe common general knowledge in any country in the world.

1.-30. (canceled)
 31. A composition of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(2-(1-propyl-1H-imidazol-5-yl)acetyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH), or an enantiomer, a stereoisomer, ora combination thereof, with a purity of ≥96.0% or ≥98.5% or higher,wherein said compound comprises one or more of the following: (a) about≤0.50% to about ≥0.30% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); (b) about ≤0.50% to about ≥0.30% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX); (c) about ≤0.50% to about ≥0.30% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A); (d) about ≤0.50% to about ≥0.30%of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B); (e) about ≤0.50% to about ≥0.45%of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C); (f) about ≤0.50% to about ≥0.45%of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E); (g) about ≤0.50% to about ≥0.45%of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F); and (h) about ≤0.50% to about≥0.45% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G).
 32. The composition of claim 31,further comprising ≤1.0% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH).
 33. The composition of claim 32, wherein ≤0.50%of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH) is present.
 34. The composition of claim 31,further comprising 2000 ppm or less of4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III).35. The composition of claim 34, wherein4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) ispresent in 1500 ppm or less.
 36. The composition of claim 31, furthercomprising ≤2.0% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D).
 37. The composition of claim 36,wherein ≤1.0% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D) is present.
 38. The composition ofclaim 31, wherein ≤0.10% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII) is present, provided there is present one or moreof compounds (b)-(h).
 39. The composition of claim 31, wherein ≤0.10% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX) is present, provided there is present one or more ofcompounds (a) and (c)-(h). 40.-45. (canceled)
 46. The composition ofclaim 31, said compound comprises one or more of the following: (i)≤0.30% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound II-OH); (ii) ≤0.05% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid) (Compound VIII); and (iii) ≤0.05% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylicacid (Compound IX), provided there is present one or more of compounds(c)-(h)
 47. The composition of claim 31, said compound comprises one ormore of the following: (i) 1300 ppm or less wherein4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III);(ii) ≤0.10% of8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-A); (iii) ≤0.10% of1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-B); (iv) ≤0.20% of8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-C); (v) ≤0.80% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-D); (vi) ≤0.20% of8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-E); (vii) ≤0.15% of8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate (Compound I-MsOH-F); and (viii) ≤0.10% of8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide)dimethanesulfonate (Compound I-MsOH-G), provided there is present one ormore of compounds (a)-(b).
 48. The composition of claim 31, whereinmesylate ester resulting from MsOH is present in 0.001% or less, or 10ppm or less.
 49. The composition of claim 31, wherein said compound is(S)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((S)-Compound I-MsOH).
 50. The composition of claim 49,wherein ≤0.5% of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH) is present.
 51. The compositionof claim 50, wherein ≤0.2% of(R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamidemethanesulfonate ((R)-Compound I-MsOH) is present.
 52. The compositionof claim 51, comprising 5.0% w/w or less or 2.0% w/w or less watercontent. 53.-59. (canceled)